Substituted 6,11-ethano-6,11-dihydrobenzo[b] quinolizinium salts and compositions and methods of use thereof

ABSTRACT

Substituted 6,11-ethano-6,11-dihydrobenzo[b]quinolizinium salts, pharmaceutical compositions containing them, and methods for the treatment of neurodegenerative disorders or neurotoxic injuries utilizing them, wherein the substituted 6,11-ethano-6,11-dihydrobenzo[b]quinolizinium salts have the formula: ##STR1## wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X and p are as defined in the specification.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our prior application Ser.No. 08/121,127, filed Sep. 14, 1993, now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The invention relates to substituted6,11-ethano-6,11-dihydrobenzo[b]quinolizinium salts, to pharmaceuticalcompositions containing the same and to the method of use thereof in thetreatment or prevention of neurodegenerative disorders or neurotoxicinjuries.

(b) Information Disclosure Statement

Fields, U.S. Pat. No. 3,517,073 issued Jun. 23, 1970, disclosescompounds of the formula: ##STR2## wherein each of R¹, R², R³ and R⁴when taken separately, is hydrogen, lower alkyl, lower aryl, loweracyloxy, lower alkoxy, nitro, halogen, lower acylamino, di(lower alkyl)amino; one group of R¹ and R², R² and R³, and R³ and R⁴, preferably R¹and R², and R³ and R⁴, each group when taken together, represents afused ring system containing up to three 6-member carbocyclic andnitrogen-containing heterocyclic rings at least one of which is anaromatic ring, and having no more than two nuclear nitrogens in anyring, which may be unsubstituted or substituted with one or more of thesubstituents defined by R¹, R², R³ and R⁴ ; each of R⁵ and R⁶, whentaken separately is hydrogen, lower alkyl or lower aryl; each of R⁷ andR⁸, when taken separately, is hydrogen; R⁷ and R⁸, when taken together,represent a fused ring system as defined hereinbefore; R⁹, when takenindividually, is methylene or lower alkyl, lower aryl, lower alkenyl,halogen, or cyano substituted methylene; R¹⁰, when taken individually,is a protected carbonyl group; R⁹ and R¹⁰, when taken together,represent a fused aromatic carbocyclic or heterocyclic ring system,whose valence bonds are from adjacent carbons, containing up to three6-membered carbocyclic and nitrogen-containing heterocyclic rings havingno more than two nitrogens in any ring and which may be substituted withone or more of the substituents defined by R¹, R², R³ and R⁴. Among thecompounds specifically disclosed are12,12-diethoxy-11-methyl-9,10-ethano-9,10-dihydro-4a-azoniaanthraceneperchlorate and9,10-(O-benzeno)-9,10-dihydro-5-methyl-4a-azoniaanthracene perchlorate.Also disclosed are compounds of the formula: ##STR3## wherein R¹ -R¹⁰are as defined above and m is an odd integer having a value of from 1 to5, inclusive. Among the compounds specifically disclosed are12,12-diethoxy-11-methyl-9,10-ethano-4a-aza-1,2,3,4,4a,9,9a,10-octahydroanthraceneperchlorate acid salt,9,10(O-benzeno-5-methyl-4a,-aza-1,2,3,4,4a,9,9a,10-octahydroanthraceneand 12,12-diethoxy-9,10-ethano-11-bromo-4a-aza-1,2,3,4,4a,9,9a,10-octahydroanthracene. The above-described compounds aredisclosed as being intermediates in the synthesis of 2-naptholderivatives and various anthracene derivatives.

Fields et al., J. Org. Chem. 1968, 33(1), 390-395, disclose a series ofsixteen Diels-Alder adducts prepared from a 4a-azoniaanthracene ion andvarious dienophiles. Among the compounds specifically disclosed are12-ethyl,12-hydroxymethyl and12-ethylene-9,10-dihydro-4a-azonia-9,10-ethanoanthracene bromides;12-phenyl- 12-(4-morpholinyl), 12-methyl-12-(1-methylethylene),12,12-diethoxy-11-bromo and12-diethylamino-11-phenyl-9,10-dihydro-4a-azonia-9,10-ethanoanthraceneperchlorates, as well as 9,10[1',2']cyclopentyl and9,10[2',3']tetrahydropyranyl-9,10-dihydro-4a-azoniaanthraceneperchlorates. No utility is disclosed for these compounds.

Fields and Regan, J. Org. Chem. 1971, 36(20), 2986-2990, disclosecompounds of the formula: ##STR4## wherein R is H, Br, or OAc, asintermediates in the synthesis of substituted8-tert-butyl-1-(2-pyridyl)napthalenes.

Fields and Regan, J. Org. Chem. 1971, 36(20), 2991-2994, disclosecompounds of the formula: ##STR5## wherein R is H, CH₃, C₆ H₅, or Br, asintermediates in the synthesis of 2-pyridylnapthols.

Fields, J. Org. Chem. 1971, 36(20), 3002-3005, discloses a series ofsubstituted 12,12-diethoxy-9,10-ethano-9,10-dihydro-4a-azoniaanthracenesand the corresponding derivatives wherein the pyridinium moiety ispartially or completely reduced, as intermediates in the synthesis ofsubstituted 2-napthols. Among the compounds specifically disclosed is12,12-diethoxy-5,11-dimethyl-9,10-ethano-9,10-dihydro-4a-azoniaanthraceneperchlorate. Also disclosed is a series of substituted9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracenes and the correspondingderivatives wherein the pyridinium moiety is partially or completelyreduced, as intermediates in the synthesis of substituted anthracenes.Among the compounds specifically disclosed is9,10-(O-benzeno)-9,10-dihydro-4a-azoniaanthracene perchlorate.

Westerman and Bradsher, J. Org. Chem. 1971, 36(7), 969-970, disclosecompounds of the formula: ##STR6## wherein R is CH₃, CH(CH₃)₂, H, F, I,Cl, Br, CO₂ H, CO₂ CH₃, or NO₂. No utility is disclosed for thesecompounds.

Bradsher and Day, J. Het. Chem. 1973, 10, 1031-1033, disclose fourDiels-Alder adducts prepared from acridizinium perchlorate andcyclopentadiene, methyl vinyl ether, norbomadiene and maleic anhydride.No utility is disclosed for these compounds.

Fields and Regan, J. Org. Chem. 1970, 35(6), 1870-1875, disclosecompounds of the formula: ##STR7## wherein R is H, CH₃ or C₆ H₅. Alsospecifically disclosed are9,10-dihydro-12,12-dimethoxy-11,11-dimethyl-4a-azonia-9,10-ethanoanthraceneperchlorate and9,10-dihydro-9,11-dimethyl-12,12-diethoxy-4a-azonia-9,10-ethanoanthraceneperchlorate. The compounds are said to be intermediates in the synthesisof 9,10-dihydro-12-oxo-4a-azonia-9,10-ethanoanthracenes.

Fields et al., J. Org. Chem. 1971, 36(20), 2995-3001, disclose9,10-dihydro-4a-azonia-9,10-O-benzenoanthracene perchlorate and severalanalogs as intermediates in the synthesis of various9-(2-pyridyl)anthracenes.

Fields and Miller, J. Het. Chem. 1970, 7, 91-97, disclose a compound ofthe formula: ##STR8## as an intermediate in the synthesis of thecorresponding 5,8-dione salt.

Bradsher and Stone, J. Org. Chem. 1968, 33(2), 519-523, disclose aseries of Diels-Alder adducts prepared from an acridizinium ion andmaleic anhydride, maleate esters, fumarate esters and variouspara-substituted styrenes in which the para substituent is H, CH₃, OCH₃or NO₂. No utility is disclosed for these compounds. A substantiallysimilar disclosure for the preparation of Diels-Alder adducts fromacridizinium bromide and maleic anhydride, maleate or fumarate esterscan be found in Bradsher and Solomons, J. Am. Chem. Soc. 1958, 80,933-934.

Bradsher and Stone, J. Org. Chem. 1969, 34(6), 1700-1702, disclosecompounds of the formula: ##STR9## wherein R is H, or CH₃ ; R' is H, orCH₃ ; R" is OCH₃, CH₃, H, or NO₂ ; and X⁻ is perchlorate; without anindication of utility. Also disclosed are the Diels-Alder adductsobtained from acridizinium perchlorate and diethyl maleate, diethylfumarate or dimethyl maleate, without an indication of utility.

Burnham and Bradsher, J. Org. Chem. 1972, 37(3), 355-358, disclosecompounds of the formula: ##STR10## wherein R¹ is Ph, and R² is OEt; orR¹ is H, and R² is OEt, OBu, OAc, N-carbazolyl or 1-pyrrolidin-2-one,without an indication of utility

Parham et al., J. Org. Chem. 1972, 37(3), 358-362, disclose compounds ofthe formula: ##STR11## wherein R is H₂, (CH₂)₃, C(O)NHC(O),C(O)N(CH₃)C(O), C(O)OC(O), CH₂ OCH₂, or CH₂ NH₂ +CH₂, without anindication of utility.

Bradsher et al., J. Am. Chem. Soc. 1977, 99(8), 2588-2591, disclosecompounds of the formula: ##STR12## wherein: R¹ =R² =R⁴ =R⁵ =H; R¹ =Me,and R² =R⁴ =R⁵ =H; R¹ =R⁴ =R⁵ =H, and R² =Me; and R¹ =H, and R² =R⁴ =R⁵=Me. No utility is disclosed for these compounds.

Bradsher et al., J. Org. Chem. 1978, 43(5), 822-827, disclose compoundsof the formula: ##STR13## wherein: R¹ is OEt and R is Me, H, F, Cl, CO₂Me or NO₂ ; R¹ is O-Ph-p-X, wherein X is CH₃, OCH₃, H, C(O)CH₃, or NO₂,and R is hydrogen; and R¹ is N-carbazolyl and R is hydrogen. No utilityis disclosed for these compounds.

Westerman and Bradsher, J. Org. Chem. 1978, 43(15), 3002-3006, disclosea series of Diels-Alder adducts prepared from an acridizinium ion andvarious unsymmetrical alkenes, without an indication of utility. Amongthe compounds specifically disclosed are6,11[2',3']indanyl-6,11-dihydroacridizinium tetrafluoroborate, and12-phenyl-13-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridiziniumtetrafluoroborate.

Westerman and Bradsher, J. Org. Chem. 1979, 44(5), 727-733, disclose aseries of Diels-Alder adducts prepared from a substituted orunsubstituted acridizinium cation and various polarizable alkeneswithout an indication of utility. Among the compounds specificallydisclosed are 12,12-diphenyl-6,11-dihydro-6,11-ethanoacridiziniumperchlorate or bromide, 9-methyl-6,11[2'3']indanyl-6,11-dihydroacridizinium tetrafluoroborate, and7,10-dimethyl-12-phenyl-12-(4-morpholinyl), 9-methyl- 12-phenyl-12-(4-morpholinyl), 12-(2-pyridyl), and9-methyl-12-(2-pyridyl)-6,11-dihydro-6,11-ethanoacridiziniumtetrafluoroborates.

Bradsher et al., J. Org. Chem. 1979, 44(8), 1199-1201, disclose a seriesof Diels-Alder adducts prepared from a substituted or unsubstitutedacridizinium ion and cyclopropene or 1-methylcyclopropene, without anindication of utility.

Hart et al., Tetrahedron Letters 1975, 52, 4639-4642, disclose acompound of the formula: ##STR14## as an intermediate in the synthesisof 1,4,5,8,9-pentamethylanthracene.

SUMMARY OF THE INVENTION

The invention relates to compounds of the Formula I: ##STR15##

R¹ is hydrogen, or from one to four, the same or different, substituentsin any of the 1-,2-,3- or 4- positions selected from the groupconsisting of lower-alkoxy, lower-alkyl, halogen, hydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy,OC(O)alkylC(O)Oalkyl, hydroxymethyl, nitro, amino andlower-alkylsulfonylamino or R¹ is a fused benzene ring;

R² is hydrogen, lower-alkyl, cyano or lower-alkoxycarbonyl;

R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower-alkylidene group;

R⁵ and R⁶ are independently hydrogen phenyl (or phenyl substituted bylower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl,lower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-, hydroxy, orpolychlorolower-alkyl), a 5- or 6-membered monocyclic or 9- or10-membered bicyclic aromatic heterocyclic ring system or a 5- or6-membered monocyclic nonaromatic heterocyclic ring system (or said 5-or 6- membered monocyclic or 9- or 10-membered bicyclic aromaticheterocyclic ring system or said 5- or 6- membered monocyclicnonaromatic heterocyclic ring system substituted on any available carbonatom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, orlower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl,phenyl-lower-alkyl (or said phenyl lower-alkyl group substituted on thephenyl group by lower-alkoxy, lower-alkyl, or halogen),trilower-alkylsilyl, lower-alkylphenylsulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl), lower-alkoxy, orlower-alkynyl; or R⁵ and R⁶ together form a fluorene ring;

or R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the formula A:##STR16## wherein A is phenyl, or a 5- or 6-membered monocyclic aromaticheterocyclic ring system and n is an integer from one to three (or saidA ring substituted on any available carbon atom thereof by lower-alkoxy,or lower-alkyl);

R⁷ is hydrogen, or from one to four, the same or different, substituentsin any of the 7-, 8-, 9-, or 10- positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylene-dioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H;PO₃ ⁻ cyano, polychlorolower-alkyl, OC(O)alkyl-CH═CH-alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,halomethyl, hydroxymethyl, amino and lower-alkylsulfonylamino wherein mis an integer from one to four and/or R⁷ is a fused pyrazole ring;

X⁻ is an anion; and p is zero when R⁷ is a negatively charged radicaland p is one when R⁷ is other than a negatively charged radical; or apharmaceutically acceptable acid-addition salt of basic members thereof;or a solvate thereof; or a stereoisomer thereof; with the followingprovisos a) at least one of R⁵ and R⁶ when taken individually must be asubstituted or unsubstituted phenyl group, or a substituted orunsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclicaromatic heterocyclic ring system or a substituted or unsubstituted 5-or 6-membered nonaromatic heterocyclic ring system; b) when R³ and R⁵ orR⁴ and R⁶ together form a bicyclic ring system of formula A wherein A isphenyl and n is 1; R¹,R²,R⁴, and R⁶ or R¹,R²,R³ and R⁵, respectively arehydrogen and X⁻ is BF₄ ⁻, R⁷ is other than hydrogen or 9-methyl; c) whenR¹,R²,R³, and R⁴ are hydrogen; R⁵ and R⁶ are phenyl, and X⁻ is ClO₄ ⁻ orBr⁻ ; R⁷ is other than hydrogen, d) when R¹,R²,R³, and R⁴ are hydrogen;one of R⁵ or R⁶ is phenyl, and one of R⁵ or R⁶ is methoxy; and X⁻ is BF₄⁻, R⁷ is other than hydrogen or 9-methyl; and e) when R¹,R²,R³, and R⁴are hydrogen; R⁵ is 4-morpholinyl and R⁶ is phenyl or R⁵ is phenyl andR⁶ is 4-morpholinyl; and X⁻ is ClO₄ ⁻, Br⁻ or BF₄ ⁻, R⁷ is other thanhydrogen, 9-methyl, or 7,10-dimethyl.

The compounds of the Formula I bind to the PCP receptor and are thususeful in the treatment or prevention of neurodegenerative disorders orneurotoxic injuries.

Compounds within the ambit of Formula I above are those wherein:

R¹ is hydrogen, or from one to four, the same or different, substituentsin any of the 1-, 2-, 3- or 4- positions selected from the groupconsisting of lower-alkoxy, lower-alkyl, and halogen;

R² is hydrogen, or lower-alkyl;

R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower alkylidene group;

R⁵ and R⁶ are independently hydrogen phenyl (or phenyl substituted bylower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl,lower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-, hydroxy, orpolychloroloweroalkyl), a 5- or 6-membered monocyclic or 9- or10-membered bicyclic aromatic heterocyclic ring system or a 5- or6-membered monocyclic nonaromatic heterocyclic ring system (or said 5-or 6- membered monocyclic or 9- or 10-membered bicyclic aromaticheterocyclic ring system or said 5- or 6- membered monocyclicnonaromatic heterocyclic ring system substituted on any available carbonatom thereof by lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or onany available nitrogen atom thereof by lower-alkyl, phenyl-lower-alkyl(or said phenyl lower-alkyl group substituted on the phenyl group bylower-alkoxy, lower-alkyl, or halogen), trilower-alkylsilyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl), lower-alkoxy, orlower-alkynyl; or R⁵ and R⁶ together form a fluorene ring;

or R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the formula A:##STR17## wherein A is phenyl, or a 5- or 6-membered monocyclic aromaticheterocyclic ring system and n is an integer from one to three (or saidA ring substituted on any available carbon atom thereof by lower-alkoxy,or lower-alkyl);

R⁷ is hydrogen, or from one to four, the same or different, substituentsin any of the 7-, 8-, 9-, or 10- positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H,PO₃ ⁻, cyano, and polychlorolower-alkyl, wherein m is an integer fromone to four;

X⁻ is an anion; and p is zero when R⁷ is a negatively charged radicaland p is one when R⁷ is other than a negatively charged radical; or apharmaceutically acceptable acid-addition salt of basic members thereof;or a solvate thereof; or a stereoisomer thereof; with the followingprovisos a) at least one of R⁵ and R⁶ when taken individually must be asubstituted or unsubstituted phenyl group, or a substituted orunsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclicaromatic heterocyclic ring system or a substituted or unsubstituted 5-or 6-membered nonaromatic heterocyclic ring system; b) when R³ and R⁵ orR⁴ and R⁶ together form a bicyclic ring system of formula A wherein A isphenyl and n is 1; R¹,R²,R⁴, and R⁶ or R¹,R²,R³ and R⁵, respectively arehydrogen and X-- is BF₄ --, R⁷ is other than hydrogen or 9-methyl; c)when R¹,R²,R³, and R⁴ are hydrogen; R⁵ and R⁶ are phenyl, and X⁻ is ClO₄⁻ or Br⁻ ; R⁷ is other than hydrogen, d) when R¹,R²,R³, and R⁴ arehydrogen; one of R⁵ or R⁶ is phenyl, and one of R⁵ or R⁶ is methoxy; andX⁻ is BF₄ ⁻, R⁷ is other than hydrogen or 9-methyl; and e) whenR¹,R²,R³, and R⁴ are hydrogen; R⁵ is 4-morpholinyl and R⁶ is phenyl orR⁵ is phenyl and R⁶ is 4-morpholinyl; and X⁻ is ClO₄ ⁻, Br⁻ or BF₄ ⁻, R⁷is other than hydrogen, 9-methyl, or 7,10-dimethyl.

Preferred compounds of the Formula I above are those wherein:

R¹,R²,R³ and R⁴, taken independently or together, and X⁻ are as defineddirectly hereinabove; R⁵ and R⁶ are independently phenyl (or phenylsubstituted by lower-alkoxy, halogen, lower-alkyl,polyfluorolower-alkyl, orlower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-), a 5- or6-membered monocyclic or 9- membered bicyclic aromatic heterocyclic ringsystem (or said 5- or 6-membered monocyclic or 9-membered bicyclicaromatic heterocyclic ring system substituted on any available carbonatom thereof by lower-alkyl, oxo, or lower-alkoxy; or on any availablenitrogen atom thereof by lower-alkoxyphenyl-lower-alkyl,trilower-alkylsilyl, or trilower-alkylsilyl-lower-alkoxy-lower-alkyl),lower-alkoxy, or lower-alkynyl; or R⁵ and R⁶ together form a fluorenering;

R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the Formula A:##STR18## wherein A is phenyl, or a 5-membered monocyclic aromaticheterocyclic ring system and n is an integer from one to two (or said Aring substituted on any available carbon atom thereof by lower-alkoxy,or lower-alkyl) and R⁷ is hydrogen, or from one to four, the same ordifferent, substituents in any of the 7-, 8-, 9-, or 10- positionsselected from the group consisting of lower-alkyl, lower-alkanoyloxy,halogen, nitro, hydroxy, lower-alkoxy, methylenedioxy,perfluorolower-alkyl, SO₃ ⁻, and polychlorolower-alkyl.

Particularly preferred compounds of the Formula I above are thosewherein:

R², R³ and R⁴ taken independently or together, and X⁻ are as defineddirectly hereinabove;

R¹ is hydrogen, or one lower-alkyl substituent in any of the 1-, 2-, 3-or 4- positions;

R⁷ is hydrogen, or from one to two, the same or different, substituentsin any of the 7-, 8-, 9-, or 10- positions selected from the groupconsisting of halogen, hydroxy, lower-alkoxy, SO₃ ⁻ andpolyfluorolower-alkyl; R⁵ and R⁶ are independently phenyl (or phenylsubstituted by lower-alkoxy, halogen, lower-alkyl, trifluoromethyl, orlower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-), a 5- or6-membered monocyclic or 9-membered bicyclic aromatic heterocyclic ringsystem selected from the group consisting of furanyl, benzofuranyl,pyridinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl andpyrrolyl (or said 5- or 6- membered monocyclic or 9-membered bicyclicaromatic heterocyclic ring system substituted on any available carbonatom thereof by lower-alkyl, oxo or lower-alkoxy; or any availablenitrogen atom thereof by lower-alkoxyphenyl-lower-alkyl, ortrilower-alkylsilyl, trilower-alkylsilyl-lower-alkoxy-lower-alkyl),lower-alkoxy, or lower-alkynyl; or R⁵ and R⁶ together form a fluorenering; and

R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the Formula A:##STR19## wherein A is phenyl, or a 5-membered monocyclic aromaticheterocyclic ring system selected from the group consisting of furanyl,isoxazoyl and thienyl (or said A ring substituted on any availablecarbon atom thereof by lower-alkoxy, or lower-alkyl).

Other preferred compounds of the Formula I above are those wherein:

R¹ is hydrogen or one lower-alkoxy or halogen substituent in any of the1-, 2-, 3-, or 4- positions;

R² is hydrogen or lower-alkyl;

R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower-alkylidene group;

R⁵ and R⁶ are independently phenyl substituted by hydroxy or a 5- or 6-membered monocyclic aromatic heterocyclic ring system selected from thegroup consisting of pyrazolyl, triazolyl, pyridinyl, furanyl,imidazolyl, and pyrrolyl (or said 5- or 6- membered monocyclic aromaticheterocyclic ring system substituted on any available carbon atomthereof by lower-alkoxy, or on any available nitrogen atom thereof bylower-alkyl, lower-alkoxyphenyl-loweralkyl, or trilower-alkylsilyl);

R⁷ is hydrogen, or from one to two, the same or different, substituentsin any of the 7-, 8-, 9- or 10- positions selected from the groupconsisting of OC(O)alkyl, OCO(CH₂)_(m) C(O)alkyl, hydroxy, lower-alkoxy,methylenedioxy, halogen and nitro; and

X and p are as defined hereinabove.

Other compounds of the Formula I above are those wherein:

R¹ is from one to four, the same or different, substituents in any ofthe 1-, 2-, 3- or 4- positions selected from the group consisting ofhydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O)alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,hydroxymethyl, nitro, amino and lower-alkylsulfonylamino; or R¹ is afused benzene ring; and R², R³, R⁴, R⁵, R⁶, R⁷, m, n, x⁻ and p are asdefined hereinabove on pages 8-9.

Preferred compounds of the Formula I within this latter group are thosewherein:

R¹ is one substituent in any of the 1-, 2-, 3-, or 4- positions selectedfrom the group consisting of hydroxy and OC(O) alkyl; or R¹ is a fusedbenzene ring;

R², R³, R⁴ and R⁷ are hydrogen;

R⁵ and R⁶ are independently a 5- or 6- membered monocyclic aromaticheterocyclic ring system selected from the group consisting of furanyl,pyridinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrrolyland imidazolyl; and

X⁻ is an anion.

Still other compounds of the Formula I above are those wherein:

R² is cyano or lower-alkoxycarbonyl; and

R₁, R³, R⁴, R⁵, R⁶, R₇, n, m, x-, and p are as defined hereinabove onpages 8-9.

Preferred compounds of the Formula I within this latter group are thosewherein:

R² is cyano or lower-alkoxycarbonyl;

R¹, R³, R⁴ and R⁷ are hydrogen;

R⁵ and R⁶ are independently selected from the group consisting offuranyl, pyridinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,pyrrolyl and imidazolyl; and

X⁻ is an anion.

Still other compounds of the Formula I above are those wherein:

R¹, R², R³, R⁴, R⁵, R⁶, n, m, x- and p are as defined hereinabove onpages 8-9; and,

R⁷ is from one to four, the same or different, substituents in any ofthe 7-, 8-, 9- or 10- positions selected from the group consisting ofOC(O)alkylCH═CH-alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy,OC(O)alkylC(O)O alkyl, halomethyl, hydroxymethyl, amino andlower-alkylsulfonylamino; and/or R⁷ is a fused pyrazole ring.

Preferred compounds of the Formula I within this latter group are thosewherein:

R¹, R², R³ and R⁴ are hydrogen;

R⁵ and R⁶ are independently a 5- or 6- membered monocyclic aromaticheterocyclic ring system selected from the group consisting of furanyl,pyridinyl, thienyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, pyrrolyland imidazolyl;

R⁷ is as defined directly hereinabove; and

X⁻ is an anion.

The invention further relates to pharmaceutical compositions whichcomprise a compound of the Formula I: ##STR20## wherein:

R¹ is hydrogen, or from one to four, the same or different, substituentsin any of the 1-, 2-, 3- or 4⁻ positions selected from the groupconsisting of lower-alkoxy, lower-alkyl, halogen, hydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy,OC(O)alkylC(O)Oalkyl, hydroxymethyl, nitro, amino andlower-alkylsulfonylamino or R¹ is a fused benzene ring;

R² is hydrogen, lower-alkyl, cyano or lower-alkoxycarbonyl;

R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower-alkylidene group;

R⁵ and R⁶ are independently hydrogen phenyl (or phenyl substituted bylower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl,lower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-, hydroxy, orpolychlorolower-alkyl), a 5- or 6-membered monocyclic or 9- or10-membered bicyclic aromatic heterocyclic ring system or a 5- or6-membered monocyclic nonaromatic heterocyclic ring system (or said 5-or 6- membered monocyclic or 9- or 10-membered bicyclic aromaticheterocyclic ring system or said 5- or 6- membered monocyclicnonaromatic heterocyclic ring system substituted on any available carbonatom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, orlower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl,phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on thephenyl group by lower-alkoxy, lower-alkyl, or halogen),trilower-alkysilyl, lower-alkylphenylsulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl), lower-alkoxy, orlower-alkynyl; or R⁵ and R⁶ together form a fluorene ring;

or R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the formula A:##STR21## wherein A is phenyl, or a 5- or 6-membered monocyclic aromaticheterocyclic ring system and n is an integer from one to three (or saidA ring substituted on any available carbon atom thereof by lower-alkoxy,or lower-alkyl);

R⁷ is hydrogen, or from one to four, the same or different, substituentsin any of the 7-, 8-, 9-, or 10- positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H;PO₃ ⁻ cyano, polychlorolower-alkyl, OC(O)alkyl-CH═CH-alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,halomethyl, hydroxymethyl, amino and lower-alkylsulfonylamino; wherein mis a integer from one to four; and/or R⁷ is a fused pyrazole ring;

X⁻ is an anion; and p is zero when R⁷ is a negatively charged radicaland p is one when R⁷ is other than a negatively charged radical;

or a pharmaceutically acceptable acid-addition salt of basic membersthereof; or a solvate thereof; or a stereoisomer thereof; together witha pharmaceutically acceptable carrier, adjuvant, diluent or vehicle,with the proviso that at least one of R⁵ and R⁶ when taken individuallymust be a substituted or unsubstituted phenyl group, or a substituted orunsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclicaromatic heterocyclic ring system or a substituted or unsubstituted 5-or 6-membered monocyclic nonaromatic heterocyclic ring system.

The invention further relates to a method for the treatment orprevention of neurodegenerative disorders, or neurotoxic injuries whichcomprises administering to a patient in need of such treatment aneffective amount of a compound of the formula I: ##STR22## wherein:

R¹ is hydrogen, or from one to four, the same or different, substituentsin any of the 1-, 2-, 3- or 4- positions selected from the groupconsisting of lower-alkoxy, lower-alkyl, halogen hydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy,OC(O)alkylC(O)Oalkyl, hydroxymethyl, nitro, amino andlower-alkylsulfonylamino or R¹ is a fused benzene ring;

R² is hydrogen, lower-alkyl, cyano or lower-alkoxycarboxy;

R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower-alkylidene group;

R⁵ and R⁶ are independently hydrogen phenyl (or phenyl substituted bylower-alkoxy, halogen, lower-alkyl, polyfluorolower-alkyl,lower-alkoxyphenyl-lower-alkyl-N(lower-alkylsulfonyl)-, hydroxy, orpolychlorolower-alkyl), a 5- or 6-membered monocyclic or 9- or10-membered bicyclic aromatic heterocyclic ring system or a 5- or6-membered monocyclic nonaromatic heterocyclic ring system (or said 5-or 6- membered monocyclic or 9- or 10-membered bicyclic aromaticheterocyclic ring system or said 5- or 6- membered monocyclicnonaromatic heterocyclic ring system substituted on any available carbonatom thereof by hydroxy, lower-alkyl, oxo, nitro, halogen, orlower-alkoxy; or on any available nitrogen atom thereof by lower-alkyl,phenyl-lower-alkyl (or said phenyl-lower-alkyl group substituted on thephenyl group by lower-alkoxy, lower-alkyl, or halogen),trilower-alkysilyl, lower-alkylphenylsulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl), lower-alkoxy, orlower-alkynyl; or R⁵ and R⁶ together form a fluorene ring;

or R³ and R⁵, and/or R⁴ and R⁶ taken together with the carbon atoms towhich they are attached form a bicyclic ring system of the formula A:##STR23## wherein A is phenyl, or a 5- or 6-membered monocyclic aromaticheterocyclic ring system and n is an integer from one to three (or saidA ring substituted on any available carbon atom thereof by lower-alkoxy,or lower-alkyl);

R⁷ is hydrogen, or from one to four, the same or different, substituentsin any of the 7-, 8-, 9-, or 10- positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H,PO₃ ⁻, cyano, polychloro-loweralkyl, OC(O)alkyl-CH═CH-alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O) alkyl C(O)O alkyl,halomethyl, hydroxymethyl, amino and lower-alkylsulfonylamino; wherein mis an integer from one to four; and/or R⁷ is a fused pyrazole ring;

X⁻ is an anion; and p is zero when R⁷ is a negatively charged radicaland p is one when R⁷ is other than a negatively charged radical;

or a pharmaceutically acceptable acid-addition salt of basic membersthereof; or a solvate thereof; or a stereoisomer thereof; with theproviso that at least one of R⁵ and R⁶ when taken individually must be asubstituted or unsubstituted phenyl group, or a substituted orunsubstituted 5- or 6-membered monocyclic or 9- or 10-membered bicyclicaromatic heterocyclic ring system or a substituted or unsubstituted 5-or 6-membered monocyclic nonaromatic heterocyclic ring system.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

The term lower-alkyl as used herein means linear or branched hydrocarbonchains having one to about four carbon atoms and thus includes methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, and the like.

The term lower-alkoxy as used herein means linear or branched alkyloxysubstituents having one to about four carbon atoms and thus includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and the like.

The term alkyl as used herein means linear or branched hydrocarbonchains having one to about sixteen carbon atoms and thus includesmethyl, ethyl, 1,1-dimethylethyl, propyl, isopropyl, n-butyl, sec-butyl,t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl,neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl,2-ethylbutyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, n-octyl,2,4,4-trimethylpentyl, n-nonyl, 3,5,5-trimethylhexyl, n-decyl,3,7-dimethyloctyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl,n-pentadecyl, n-hexadecyl, and the like.

The term alkoxy as used herein means linear or branched alkyloxysubstituents having from one to about sixteen carbon atoms and thusincludes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,t-butoxy, n-pentyloxy, 2-methyl-3-butyloxy, 1-methylbutytoxy,2-methylbutyloxy, neopentyloxy, n-hexyloxy, 1-methylpentyloxy,3-methylpentyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 2-hexyloxy,3-hexyloxy, n-heptyloxy, 2-heptyloxy, n-octyloxy,2,4,4-trimethylpentyloxy, n-nonyloxy, 3,5,5-trimethylhexyloxy,n-decyloxy, 3,7-dimethyloctyloxy, n-undecyloxy, n-dodecyloxy,n-tridecyloxy, n-tetradecyloxy, n-pentadecyloxy, n-hexadecyloxy, and thelike.

The term halogen, halo, or halide as used herein means bromine,chlorine, iodine, or fluorine.

The term lower-alkanoyloxy as used herein means linear or branchedhydrocarbon chains having two to about four carbon atoms and thusincludes acetyloxy, propionyloxy, isobutyryloxy, and the like.

The term cycloalkyl as used herein means C₃ to C₇ unsaturated monocyclichydrocarbon residues and thus includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term lower-aikylidene as used herein means linear or branchedhydrocarbon chains having one to about four carbon atoms and thusincludes methylidene, ethylidene, propylidene, isopropylidene,sec-butylidene, and the like.

The term lower-alkenyl as used herein means linear or branchedunsaturated hydrocarbon radicals having two to about four carbon atomsand thus includes ethenyl, 1-propenyl, 2-propenyl, isopropenyl,1-methyl-2-propenyl, 2-butenyl, isobutenyl and the like.

The term lower-alkynyl as used herein means linear or branchedunsaturated radicals having two to about four carbon atoms and thusincludes ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyland the like.

The term anion (X⁻) as used herein means the anion of an organic acid(includes anions of organic monoacids, as well as monoanions of organicdiacids) which is at least as strong as acetic acid, and thus includesanions of such acids as acetic acid, trifluoroacetic acidmethanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonicacid, (-)-dibenzoyl-L-tartaric acid [(-)-DBT], (+)dibenzoyl-D-tartaricacid [(+)-DBT], and the like; or it means an inorganic acid anion suchas chloride, bromide, perchlorate, PF₆ ⁻ and the like, preferablychloride.

The term 5- or 6-membered monocyclic aromatic heterocyclic ring systemas used herein means 5- or 6-membered monocyclic aromatic heterocyclicring systems containing from one to three, the same or different,heteroatoms selected from the group consisting of nitrogen, oxygen andsulfur (or said 5- or 6-membered monocyclic aromatic heterocyclic ringsystem substituted on any available carbon atom thereof by hydroxy,lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any availablenitrogen atom thereof by lower-alkyl, phenyl-lower-alkyl (or saidphenyl-lower-alkyl group substituted on the phenyl group bylower-alkoxy, lower-alkyl, or halogen), trilower-alkylsilyl,lower-alkylphenylsulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl). Representative examplesof such 5- or 6-membered monocyclic aromatic heterocyclic ring systemsinclude, but are not limited to, furan, pyridine, thiophene, oxazole,thiazole, pyrazole, triazole, pyrrole, imidazole, isoxazole, oxadiazole,pyrazine, pyridazine, pyrimidine, triazine, thiadiazole and the like; orsaid 5- or 6-membered monocyclic aromatic heterocyclic ring systemssubstituted on any available carbon or nitrogen atom thereof asdescribed hereinabove.

The term 5- or 6-membered monocyclic nonaromatic heterocyclic ringsystem as used herein means 5- or 6-membered nonaromatic heterocyclicring systems containing from one to two, the same or different,heteroatoms selected from the group consisting of nitrogen, oxygen andsulfur (or said 5- or 6-membered monocyclic nonaromatic heterocyclicring system substituted on any available carbon atom thereof by hydroxy,lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any availablenitrogen atom thereof by lower-alkyl, phenyl-lower-alkyl (or saidphenyl-lower-alkyl group substituted on the phenyl group bylower-alkoxy, lower-alkyl, or halogen), trilower-alkylsilyl,lower-alkylphenylsulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl). Representative examplesof such 5- or 6-membered monocyclic nonaromatic heterocyclic ringsystems include, but are not limited to, pyrrolidine, thiazolidine,tetrahydrofuran, tetrahydrothiophene, thiomorpholine, morpholine,piperazine, piperidine, tetrahydropyran, 1,4-thioxane, and the like; orsaid 5- or 6-membered monocyclic nonaromatic heterocyclic ring systemsubstituted on any available carbon or nitrogen atom thereof asdescribed hereinabove.

The term 9- or 10-membered bicyclic aromatic heterocyclic ring system asused herein means 9- or 10-membered bicyclic aromatic heterocyclic ringsystems containing from one to three, the same or different, heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur (orsaid 9- or 10-membered bicyclic aromatic heterocyclic ring systemsubstituted on any available carbon atom thereof by hydroxy,lower-alkyl, oxo, nitro, halogen, or lower-alkoxy; or on any availablenitrogen atom thereof by lower-alkyl, phenyl-lower-alkyl (or saidphenyl-lower-alkyl group substituted on the phenyl group bylower-alkoxy, lower-alkyl, or halogen), trilower-alkylsilyl,lower-alkylphenylasulfonyl, ortrilower-alkylsilyl-lower-alkoxy-lower-alkyl). Representative examplesof such 9- or 10-membered bicyclic aromatic heterocyclic ring systemsinclude, but are not limited to, benzofuran, benzimidazole,thianaphthene, benzisothiazole, quinoline, isoquinoline, quinoxaline,quinazoline, indole, 1,8-naphthyridine, benzothiazole, benzoxazole,indazole, benzotriazole and the like; or said 9- or 10-membered bicyclicaromatic heterocyclic ring system substituted on any available carbon ornitrogen atom thereof as described hereinabove.

It will be appreciated that in the compounds of the formulas I and II,X⁻ is an anion when p, in the term (X⁻)_(p), is one; however, when thecompounds of the formula I and II contain a negatively charged radical,e.g. when R⁷ is CO₂ ⁻, SO₃ ⁻, or PO₃ ⁻, p, in the term (X⁻)_(p), is zeroand the compounds exist as zwitterionic species.

The numbering system used throughout the specification is shown in thering system which is illustrated below. This ring system is usuallynamed in the chemical literature as a6,11-ethano-6,11-dihydrobenzo[b]quinolizinium or a6,11-dihydro-6,11-ethanoacridizinium. It should be noted, however, thatin some ##STR24## of the earlier chemical literature references (seereferences cited in Information Disclosure Statement) this ring systemwas numbered as shown below, and was named as a9,10-ethano-9,10-dihydro-4a-azoniaanthracene, or a9,10-dihydro-4a-azonia-9,10-ethanoanthracene. ##STR25## Throughout thisspecification, however, we will use the former numbering system, and wewill name the compounds as 6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumsalts.

The synthesis of the compounds of the invention may be outlined as shownin Scheme A: ##STR26##

A suitably substituted benzo[b]quinolizinium salt (II) in an appropriateorganic solvent, e.g. nitromethane, acetonitrile, nitropropane andlower-alkanols (e.g. methanol and ethanol) or mixtures thereof, istreated with at least one molar equivalent of a suitably substitutedolefin (III), at a temperature in the range of about 50° C. up to theboiling point of the solvent or solvent mixture used to afford thecompounds of the Formula I.

If desired, the compounds of Formula I can be converted into othercompounds of Formula I which possess various different anions (X⁻) by a)treating a compound of the Formula I with at least one molar equivalentof the alkali metal salt of an organic acid anion or an inorganic acidanion, M⁺ X⁻, wherein the acid of the salt used is a stronger acid thanthe corresponding acid of the initial acid anion (X⁻), and wherein M⁺ isan alkali metal, e.g. lithium, sodium or potassium; b) passing acompound of the Formula I wherein X⁻ is other than Cl⁻ through a Dowex®1×2-200 ion-exchange resin (Dowex®-1-chloride) column to produce thecompounds of the Formula I wherein X⁻ is Cl⁻ ; or c) by passing acompound of the Formula I through a suitable ion-exchange resin column(prepared, for example, by treating Dowex® 1×2-200 ion-exchange resinwith a suitable organic acid or inorganic acid) to provide variouscompounds of Formula I wherein X⁻ is other than Cl-, ClO₄ ⁻ or PF₆ ⁻.

It will be appreciated that the compounds of Formula I can possess oneor more asymmetric carbon atoms and are thus capable of existing in anumber of stereoisomeric forms, e.g. enantiomers, diastereomers, andgeometric isomers. Unless otherwise specified herein, the invention isintended to extend to each of these stereoisomeric forms, and tomixtures thereof, including the racemates. In some cases, there may beadvantages, e.g. greater potency, to using a particular enantiomer whencompared to the other enantiomer or the racemate in the treatment orprevention of neurodegenerative disorders or neurotoxic injuries, andsuch advantages can be readily determined by those skilled in the art.The different stereoisomeric forms may be separated one from the otherby the methods described hereinbelow.

The diastereomers/geometric isomers can be separated by conventionalprocedures which are well known in the art of chemistry such aschromatography, fractional crystallization and the like. The separationof enantiomers can be accomplished by a) chiral chromatography, or b)treating a racemic mixture of a compound of Formula I with the potassiumsalt of (+)-dibenzoyl-D-tartaric acid (K⁺ [(+)-DBT]) to afford acompound of Formula I as the ⁻ [(+)-DBT] salt; fractionalcrystallization of the ⁻ [(+)-DBT] salt to afford a single diastereomerof the ⁻ [(+)-DBT] salt, and then conversion of the single diastereomerof the ⁻ [(+)-DBT] salt into various other non-chiral anions (X⁻) byfollowing the procedures described hereinabove for the conversion ofcompounds of the Formula I into other compounds of the Formula I withvarious different anions (X⁻), to produce the compounds of the Formula Ias a single enantiomer; or c) treating a racemic mixture of a compoundof Formula I with the potassium salt of (-)-dibenzoyl-L-tartaric acid(K⁻ [(-)-DBT]) to afford a compound of Formula I as the ⁻ [(-)-DBT] saltand then proceeding as described hereinabove in part b to afford thecompounds of Formula I as the other enantiomer.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin the functional groups of the compounds of the Formula I. For example,removal of N-(lower-alkyl-lower-alkoxy-trilower-alkylsilyl),N-lower-alkoxy-phenyl-lower-alkyl, N-lower-alkylphenylsulfonyl andN-trilower-alkylsilyl protecting groups to afford the corresponding N-Hderivatives; treatment of 2-lower-alkoxy pyridine derivatives with anacid to produce the corresponding 2-oxopyridine derivatives, treatmentof alcohols with acylating agents to afford the corresponding esters,hydrolysis of nitriles to afford the corresponding acids, treatment ofacids with alcohols in the presence of a dehydrating agent to afford thecorresponding ester, treatment of halides with dialkylphosphites in thepresence of a catalyst to produce phosphonates which in turn can behydrolyzed to afford the corresponding phosphonic acid derivatives,treatment of alcohols with alkyl halides to afford the correspondingalkoxy derivatives, dealkylation of ethers to afford the correspondingalcohols, hydrolysis of alkyl halides to afford the correspondingalcohols, dehalogenation of aryl halides to afford the correspondingaryl derivatives, reduction of nitro derivatives to afford thecorresponding amino derivatives and treatment of amino derivatives withsulfonyl halides to afford the corresponding sulfonamide derivatives.

The suitably substituted benzo[b]quinolizinium salts of the Formula II,which are required for the synthesis of the compounds of the Formula I,are either known and can thus be prepared by procedures which are knownin the art of chemistry (see for example, Bradsher and Parham, J. Org.Chem., 1963, 28, 83-85; Bradsher and Jones, J. Am. Chem. Soc., 1957, 79,6033-34; Bradsher et al., J. Het. Chem. 1964, 1, 30-33; and Bradsher andParham, J. Het. Chem. 1964, 1, 121-124); or if they are novel, they canbe prepared by the procedures described in the art or those describedhereinbelow and illustrated in Schemes B,C and D. In Scheme B, at leastone molar equivalent of an appropriately substituted benzyl halide (IV),wherein Z is a halogen, preferably chlorine, bromine, or iodine, istreated with at least one mole of an appropriately substituted2-(1,3-dioxolan-2-yl)pyridine (V) in the presence or absence of asuitable organic solvent, e.g. sulfolane, at a temperature of about roomtemperature up to about 146° C., to produce the pyridinium salts ofFormula VI. If desired, the pyridinium salt (VI) can then be convertedinto other pyridinium salts of the Formula VII, wherein X⁻ has themeanings given hereinabove, by utilizing procedures similar to thosedescribed hereinabove for the preparation of compounds of the Formula Iwith various anions (X⁻). The pyridinium salt (VII), or if conversioninto various anions (X⁻) was not effected, the pyridinium salt (VI) canthen be treated with an excess of an acid, e.g. polyphosphoric acid, 48%hydrobromic acid, acetic acid, methanesulfonic acid, or mixturesthereof, at a temperature of about room temperature up to the boilingpoint of the acid or acid mixture used, to afford thebenzo[b]quinolizinium salts of Formula II. ##STR27##

Alternatively, the benzo[b]quinolizinium salts of Formula II can beprepared as shown in Scheme C. At least one molar equivalent of asuitably substituted benzyl alcohol (VIII), wherein Y is hydrogen, orhalogen, especially hydrogen or bromine, is treated with at least twomolar equivalents of a lower-alkyl alkali metal, preferably n-BuLi,optionally in the presence of at least one mole of a second base, e.g.tetra-methylethylenediamine, followed by the ##STR28## addition of atleast one molar equivalent, or preferably an excess of a suitablepyridine derivative (IX), in an organic solvent, such as ether, at roomtemperature or below, preferably at a temperature in the range of aboutroom temperature to about -45° C. to afford the diol (X). The diol (X)can then be treated with (a) an excess of trifluoromethanesulfonicanhydride ((TF)₂ O), in a suitable solvent, e.g. benzene, at atemperature in the range of about room temperature up to the boilingpoint of the solvent used to afford a compound of the Formula II whereinX⁻ is ⁻ OTF; or (b) at least one molar equivalent of a phosphorousoxyhalide, preferably phosphorous oxychloride, at a temperature in therange of about room temperature up to the boiling point of thephosphorous oxyhalide, to afford a compound of the Formula II wherein X⁻is halogen. It will be noted that the methods described hereinabove inScheme C are the preferred methods when it is desired to preparebenzo[b]quinolizinium salts of Formula II which contain substituents inthe 6- and/or 10- positions.

Alternatively, the benzo[b]quinolizinium salts of Formula II can beprepared as shown in Scheme D. ##STR29##

A suitably substituted benzyl halide (IV), is treated with at least onemole of suitably substituted pyridine derivative (IX), in the presenceof a suitable organic solvent, e.g. sulpholane, at a temperature ofabout room temperature up to the boiling point of the solvent used, toproduce a pyridinium salt (XI). The pyridinium salt (XI) can then betreated with an excess of an acid, e.g. 48% hydrobromic acid, in theabsence of a solvent, at a temperature of about room temperature up tothe boiling point of the acid used to produce the benzo[b]quinoliziniumsalt of Formula II (Z⁻ =X⁻ =halogen).

Alternatively, if a benzo[b]quinolizinium salt of the Formula II whereinR¹ is 3-hydroxy is desired, it is convenient to proceed as shown inScheme E. A suitably substituted isoquinoline derivative of the FormulaXII is treated with an excess of a haloacetone derivative of the FormulaXIII, wherein Z' is a halogen, preferably chlorine or bromine, in asuitable organic solvent, such as acetone at a temperature of about roomtemperature up to the boiling point of the solvent used, to afford theisoquinolinium salts of the Formula XIV. The isoqulinolinium salts ofthe Formula XIV can then be treated with an excess of an acid, e.g. 48%hydrobromine acid, in the absence of a solvent, at a temperature ofabout room temperature up to the boiling point of the acid used toproduct the 3-hydroxybenzo[b]quinolizinium salt of the Formula II (Z'⁻═X⁻ ═halogen). ##STR30##

If desired, the benzo[b]quinolizinium salts of Formula II can beconverted into other compounds of the Formula II which possess variousdifferent anion groups, X⁻, by following procedures similar to thosedescribed hereinabove for the conversion of the compounds of the FormulaI to various other anion groups, X⁻.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin functional groups of the compounds of Formula II. For example,dealkylation of ethers to produce the corresponding alcohols,halogenation of aryl rings to produce the corresponding aryl halides,acetylation of alcohols to produce the corresponding acetates, treatmentof alcohols with halogenating reagents to afford the correspondinghalogen derivative, and nitration of aryl rings to afford thecorresponding nito derivatives.

The appropriately substituted olefin (III), alkali metal salts of aninorganic acid anion or an organic acid anion (M⁺ X⁻), benzyl halide(IV), 2-(1,3-dioxolan-2-yl) pyridine (V), benzyl alcohol derivative(VIII), pyridine derivative (IX), isoquinoline derivative (XII) andhaloacetone derivative (XIII) are commercially available, or they can beprepared by procedures well known in the art, or by the proceduresdescribed hereinbelow in the examples.

The compounds of Formula I which contain basic substituents are usefulboth in the free base form and in the form of acid-addition salts, and,both forms are within the purview of the invention. The acid-additionsalts are often a more convenient form for use; and in practice, use ofthe salt form inherently amounts to use of the base form. The acidswhich can be used to prepare the acid-addition salts include preferablythose which produce, when combined with the free base,pharmaceutically-acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in pharmaceutical doses ofthe salts, so that the beneficial properties inherent in the free baseare not vitiated by side effects ascribable to the anions. In practicingthe present invention it is convenient to use the free base form or thehydrochloride, fumarate, toluenesulfonate, methanesulfonate or maleatesalts. However, other appropriate pharmaceutically acceptable saltswithin the scope of the invention are those derived from other mineralacids and organic acids. The acid-addition salts of the basic compoundsare prepared by standard procedures well known in the art which include,but are not limited thereto, dissolving the free base in an aqueousalcohol solution containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and an acid inan organic solvent, in which case the salt separates directly, or isprecipitated with a second organic solvent, or can be obtained byconcentration of the solution. Although medicinally acceptable salts ofthe basic compounds are preferred, all acid-addition salts are withinthe scope of the present invention. All acid-addition salts are usefulas sources of the free base form even if the particular salt per se isdesired only as an intermediate product, as, for example, when the saltis formed for purposes of purification or identification, or when it isused as an intermediate in preparing a medicinally acceptable salt by,for example, ion exchange procedures.

The compounds of Formula I are quinolizinium salts in which it ispreferred that the salts are pharmaceutically acceptable salts, that is,salts whose anions (X⁻) are relatively innocuous to the animal organismin pharmaceutical doses of the salts, so that the beneficial propertiesinherent in the compounds of the Formula I are not vitiated by sideeffects ascribable to the anions (X⁻). In practicing the presentinvention it is convenient to use the anions (X⁻) of organic acids suchas methanesulfonic acid and toluenesulfonic acid, or the anions (X⁻) ofinorganic acids such as hydrobromic acid and hydrochloric acid. However,other appropriate pharmaceutically acceptable salts within the scope ofthe invention are those derived from the anions (X⁻) of other organicacids, organic diacids, or inorganic acids.

The structures of the compounds of the invention were established by themode of synthesis, and by one or more of elemental analysis, andinfrared, nuclear magnetic resonance and mass spectroscopy. The courseof the reactions and the identity and homogeneity of the products wereassessed by one or more of thin layer chromatography (TLC), highpressure liquid chromatography (HPLC), or gas-liquid chromatography(GLC).

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points (m.p.) are given indegrees C. (°C.) and are uncorrected. The abbreviation E/PAW as usedherein means ethyl acetate in pyridine/acetic acid/water (55/20/25); TEAstands for triethylamine, TEOF stands for triethylorthoformate, DMEstands for dimethoxyethane, THF stands for tetrahydrofuran, LAH standsfor lithium aluminum hydride, MDC stands for dichloromethane, TBMEstands for tert-butylmethyl ether, TMEDA stands forN,N,N',N'-tetramethylethylene diamine, and DMPU stands for1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone.

EXAMPLE 1 (a)

To a solution of 1-indanone (23.78 g, 0.18 mol) in 250 mL of ether at 0°C. was added dropwise over 30 min, 100 mL of phenyllithium in ether(1.8M in ether) and the mixture was allowed to warm to room temperatureand stirred for 1 h. The reaction mixture was poured into a coldsaturated ammonium chloride solution, extracted with ether (2×200 mL),and the combined organic layer was washed with brine and dried oversodium sulfate. The organic solvent was removed under reduced pressure,70 mL of 20% sulfuric acid in acetic acid was added to the residue andstirred 2 min. To the above solution water (100 mL) and ether (3×200 mL)were added, The organic layer was washed with sodium bicarbonatesolution, dried over sodium sulfate, filtered, and concentrated. Toluene(300 mL) was added to the residue and the mixture was distilled(azeotropic removal of acetic acid) to afford a brown oil. The brown oilwas purified by chromatography (silica; (2:1 hexane/methylene chloride))to afford 15.58 g (45.82%) of 1-phenyl-indene as a colorless oil. Inaddition 11 g of 1-phenyl-1-acetoxy-indane was isolated as a by-product.

(b)

A mixture of 2-pyridinecarboxaldehyde (500 g, 4.67 mol), 561 mL ofethylene glycol, and 234 g of p-toluenesulfonic acid monohydrate in 5.8L of toluene was heated to reflux while distilling (azeotropic) waterformed during the reaction. The solvent was removed in vacuo and theresidue was distilled to afford 475 g (67%) of2-(1,3-dioxolan-2-yl)pyridine (Formula V: R¹ ═H).

(c)

A mixture of 716 g (4.74 mol) of 2-(1,3-dioxolan-2-yl)pyridine and 859 g(5 mol) of benzyl bromide in a 5 L flask was heated on a steam-bath to80° C. where an exothermic reaction caused the reaction temperature toreach 146° C. The reaction mixture was allowed to cool to 90° C. and themixture was heated on a steam-bath for 2 h. The reaction mixture wascooled to room temperature, the resulting solid product was heated on asteam-bath with ethyl acetate, and ethyl acetate was decanted. Thetreatment with ethyl acetate was repeated three times to afford 1526.8 gof 2-(1,3-dioxolan-2-yl)-1-benzylpyridinium bromide (Formula VI: R¹ ═R²═R⁷ ═H; Z⁻ --═Br⁻).

(d)

A mixture of 1526.8 g (4.74 mol) of2-(1,3-dioxolan-2-yl)-1-benzylpyridinium bromide in 9 L of 48% HBrsolution was heated on a steam-bath until the bromide dissolved. Themixture was heated (heating mantle) in vacuo (aspirator) to remove HBrsolution. The dry residue was suspended in 800 mL of HBr solution,cooled, and 4 L of THF was slowly added. The reaction mixture wasfiltered to afford 1080 g (87%) of benzo[b]quinolizinium bromide as agreen solid. Benzo[b]quinolizinium bromide (586 g) was dissolved in 2.4L of hot water and filtered to remove an insoluble dark material. Thefiltrate was cooled in ice-water for 4 h, filtered, and the residue waswashed with water, dried in vacuo at room temperature for 9 days toafford 508.8 g (86.8%) of benzo[b]quinolizinium bromide (Formula II: R¹═R² ═R⁷ ═H; X⁻ --═Br⁻).

(e)

Benzo[b]quinolizinium bromide (508.5 g, 1.95 mol) was dissolved in 5 Lof distilled water with heating (steam-bath). Potassiumhexafluorophosphate (367.2 g, 1.95 mol) was dissolved in 1.1 L of waterwith heating and the resulting solution was poured in portions into theabove bromide solution with steam-bath heating (20 min). The precipitatewas formed immediately and the mixture was stirred at room temperaturefor 3 h, then stirred 1 h in an ice-water bath. The solid was filtered,washed with cold water (800 mL), dried (50°-60° C.) in vacuo for 3 daysto afford 601 g (94.8%) of benzo[b]quinolizinium hexafluorophosphate.(Formula lI: R¹ ═R² ═R⁷ ═H; X⁻ --═PF₆ ⁻).

(f)

To a solution of benzo[b]quinolizinium hexafluorophosphate (4 g, 0.013mol) in 60 mL of nitromethane was added 1-phenyl-indene (3.78 g, 0.0196mol) and the mixture was heated to reflux for 3 h. The reaction mixturewas cooled, filtered, the filtrate concentrated in vacuo, and theresidue was dissolved in ether and cooled to yield a gray/white solid.The solid was filtered, dissolved in ethyl acetate/methylene chloride,and the solution was refluxed while distilling off methylene chloride.The solution was cooled, the filtered solid (NMR indicated 2.3:1isomeric mixture) was dried in vacuo at (45° C./48 h) to afford 6.95 g(94.3%) of6,11[[2',3']-3'-phenyl-indanyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR31## R⁵ ═phenyl;X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR32## R⁶ ═phenyl; X⁻═PF₆ ⁻).

EXAMPLES 2(a) AND (b)

A mixture of 4 g (0.013 mol) of benzo[b]quinoliziniumhexafluorophosphate and 2.12 g (0.0183 mol) of indene in 55 mL ofnitromethane was allowed to reflux for 36 h, cooled, and filtered toobtain a brown solid product. The solid was triturated in ether,decanted, and the residue was dried in vacuo to yield 5.6 g (87%) of asolid product (3:1 isomeric ratio). The isomeric mixture was purified bychromatography (silica/E/PAW)(2:1) and each isomer (isomer 1 and isomer2) was converted to the corresponding chloride salt by passing thehexafluorophosphate adducts through Dowex® 1×2-200 to afford 176.9 mg of6,11[[2',3']-indanyl]6,11-dihydrobenzo[b]quinolizinium chloride (FormulaI: R¹ ═R² ═R³ ═R⁵ ═H; ##STR33## X⁻ ═Cl⁻ ; Example 2(a)) isomer 1 (m.p.134°-143° C., isomeric ratio 1:15) and 178.0 mg6,11[[2',3']indanyl]6,11-dihydrobenzo[b]quinolizinium chloride (FormulaI: R¹ ═R² ═R⁴ ═R⁶ ═R⁷ ═H; ##STR34## X⁻ ═Cl⁻ ; Example 2(b)) isomer 2(m.p.240° C., isomeric ratio 10:1).

EXAMPLE 3 (a)

To a solution of 3-(4-methoxyphenyl)propionic acid (50.34 g, 0,279 mol)in 500 mL of methylene chloride cooled to 0° C. was added slowly at 0°C. 30.5 mL (0.418 mol) of thionyl chloride, the mixture was stirred 10 hat room temperature and the solvent was removed in vacuo. The residuewas dissolved in 1000 mL of methylene chloride, cooled to 0° C., and40.92 g (0.306 mol) of aluminum chloride was added in small portions andthe resulting mixture was stirred at room temperature for 1 h. The abovemixture was poured onto ice, the resulting mixture was filtered throughcelite, and the aqueous layer was extracted with methylene chloride(2×200 mL). The combined organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was extracted with hexane toafford 40 g (88%) of 6-methoxy-1-indanone.

(b)

To a solution of 20 g (0.123 mol) of 6-methoxy-l-indanone in 500 mL ofether cooled to -20° C. was added 72 mL (0.129 mol) of 1.8Mphenyllithium in cyclohexane/ether and the mixture was stirred at roomtemperature for 1 h. An additional (10 mL) phenyllithium solution wasadded and stirred at room temperature for 1 h. To the reaction mixturewas added saturated ammonium chloride solution and the resulting mixturewas extracted with ethyl acetate (3×250 mL), and the organic layer wasdried over sodium sulfate and concentrated in vacuo to afford 32.3 g ofcrude (contains solvent) 6-methoxy-1-phenyl-indan-1-ol.

(c)

To 1.5 L of toluene was added 32 g (0.133 mol) of6-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acidmonohydrate and the mixture was placed on a Rotovap and the solvent wasdistilled in vacuo (40 mm) until a brown oil residue was obtained. Thebrown oil was chromatographed (silica, 1:1 hexane/methylene chloride) toafford 17.47 g (60.2%) of 1-phenyl-6-methoxy-indene as a pale yellowoil.

(d)

A mixture of 5.6 g (0.0183 mol) of benzo[b]quinoliziniumhexafluorophosphate and 6.09 g (0.027 mol) of 1-phenyl-6-methoxyindenein 100 mL of nitromethane was heated to reflux for 12 h. The reactionmixture was cooled in ice, filtered, and concentrated in vacuo to yielda brown oil which was further concentrated in vacuo. The above brownfoam was triturated in ether, decanted, and the residue in ether wasfiltered and dried in vacuo to yield 10.0 g (99%) of6,11[[2',3']-3'-phenyl-6'-methoxyindanyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate. (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR35## R⁵═phenyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR36## R⁶═phenyl; X⁻ ═PF₆ ⁻ ; isomeric ratio 2.39:1), as a white solid, m.p.210°-216° C.

EXAMPLE 4 (a)

Dihydrocoumarin (35 g, 0.236 mol) was added to 62.9 g (0.472 mol) ofaluminum chloride and the mixture was heated in an oil-bath at 200° C.for 2.5 h with stirring. The reaction mixture was cooled, poured intoice (300 g), 300 mL of methylene chloride added to the mixture, cooled,and 400 mL of methylene chloride was added. The mixture was filtered andthe solid residue was dissolved in hot methanol, filtered, and thefiltrate was cooled to afford 14.5 g (41%) of 4-hydroxy-indan-1-one.

(b)

To a mixture of 4-hydroxy-indan-1-one (14.5 g, 0.0979 mol) and 27.08 g(0.195 mol) of potassium carbonate was added 500 mL of acetone and 48.7mL (0.78 mol) of methanol with stirring and the resulting mixture washeated to reflux for 4 h, cooled, and allowed to stand at roomtemperature for 10 h. The above mixture was filtered, concentrated undervacuo, the solid residue was dissolved in methanol, heated and filtered.The filtrate was concentrated to a volume of 100 mL, cooled and filteredto afford 12.6 g (79%) of 4-methoxy-indan-1-one.

(c)

To a solution of 9.38 g (0.057 mol) of 4-methoxy-1-indanone in 250 mL ofether cooled to 0° C. was added dropwise over 5 min 33.72 mL (0.0607mol) of 1.8M phenyllithium in cyclohexane/ether and the mixture wasstirred at room temperature for 1 h. An additional (10 mL) phenyllithiumsolution was added and stirred at room temperature for 1 h. To thereaction mixture was added saturated ammonium chloride solution and theresulting mixture was extracted with ethyl acetate (3×100 mL), and theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo to afford 14.3 g of crude4-methoxy-1-phenyl-indan-1-ol which was used directly in the next stepwithout further purification.

(d)

To 1 L of toluene was added 14 g (0.058 mol) of4-methoxy-1-phenyl-indan-1-ol and100 mg of p-toluenesulfonic acidmonohydrate and the solvent was distilled in vacuo (40 mm) until an oilyresidue was obtained. The oil was chromatographed (silica, 1:1hexane/methylene chloride followed by ether) to afford 8.6 g (60.2%) of! -phenyl-4-methoxy-indene as a pale red oil.

(e)

A mixture of 5.6 g (0.0183 mol) of benzo[b]quinoliziniumhexafluorophosphate and 6.09 g (0.027 mol) of 1-phenyl-4-methoxy-indenein 100 mL of nitromethane was heated to reflux for 6 h, cooled andfiltered. The filtrate was concentrated in vacuo, 100 mL of ether wasadded to the brown foamy residue and the resulting mixture wastriturated, a solid powder was filtered and washed with ether. Afterdrying, 9.8 g (97%) of6,11[[2',3']-3'-phenyl-7'-methoxy-indanyl]16,11-dihydrobenzo[b]quinoliziniumhexafluoro-phosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR37## R⁵═phenyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR38## R⁶═phenyl; X⁻ ═PF₆ ⁻) as a brown solid, m.p. 120°-125° C., isomeric ratio,2.7:1, was obtained.

EXAMPLE 5 (a)

To a solution of 13.17 mL (0.104 mol) of 3-bromoanisole in 150 mL ofether cooled to -78° C. was added 10.4 mL (0.104 mol) of 10Mn-butyllithium in hexane and the mixture was allowed to warm to roomtemperature (10 min). The above mixture was cooled to -20° C. and 12.5 g(0.094 mol) of indanone in 20 mL of THF was added and the mixture wasallowed to warm to room temperature, and then stirred for 1 h. To themixture was added saturated ammonium chloride solution and the resultingmixture was extracted with ethyl acetate (3×50 mL), and the organiclayer was washed with brine, dried over sodium sulfate and concentratedin vacuo to afford 23.3 g of crude 1-(3-methoxy)-phenyl-indan-1-ol, as abrown oil, which was used directly in the next step without furtherpurification.

(b)

To a mixture of 23 g (0.095 mol) of 1-(3-methoxyphenyl)-indan-1-ol and100 mg of p-toluene sulfonic acid monohydrate was added 1 L of tolueneand the solvent was distilled in vacuo (40 mm) until an oil residue wasobtained. The oil was chromatographed (silica, 1:1 hexane/methylenechloride) to afford 17.0 g (80.1%) of 1-(3-methoxyphenyl)-indene as apale yellow oil.

(c)

A mixture of 5.6 g (0.0183 mol) of benzo[b]quinoliziniumhexafluorophosphate and 6.09 g (0.027 mol) of 1-(3-methoxyphenyl)-indenein 100 mL of nitromethane was heated to reflux for 14 h, cooled andconcentrated in vacuo. The residue was triturated in ether, and a solidproduct was filtered to afford 9.8 g (98%) of6.11[[2',3']-3'-(3-methoxyphenyl)-indanyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR39## R⁵ ═3--CH₃O-phenyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ =H; ##STR40## R⁶═3--CH₃ O-phenyl; X⁻ ═PF₆ ⁻) as a grey solid, m.p.178°-185° C., isomericratio, 2.27:1.

(d)

The product of example 5 (C) was taken up in methanol (300 mL) and CH₂Cl₂ (100 mL) and heated to reflux. The mixture was cooled to roomtemperature and a solid was collected by filtration. The solid wasfractionally crystallized several times from hot methanol to afford6,11[2',3']-3'-(3-methoxyphenyl)-indanyl]16,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR41## R⁵ ═3--CH₃O-phenyl; X⁻ ═PF₆ ⁻) as a single geometric isomer.

EXAMPLE 6 (a)

To a solution of 2.7 mL (0.027 mol) of 10M n-butyllithium in hexane in70 mL of ether cooled to -78° C. was added 4 g (0.027 mol) of3-bromofuran and the mixture was stirred for 15 min. To the above cooledmixture was added 3.17 g (0.024 mol) of indanone in 10 mL of THF and themixture was allowed to warm to room temperature, and then stirred for 20min. To the mixture was added saturated ammonium chloride solution andthe resulting mixture was extracted with ethyl acetate (3×100 mL), andthe organic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo to afford 5 g of crude 1-(3-furyl)-indan-1-ol, asan orange oil, which was used directly in the next step.

(b)

To a mixture of 5 g (0.024 mol) of 1-(3-furyl)-indan-1-ol in 500 mL oftoluene was added 50 mg of p-toluenesulfonic acid monohydrate and thesolvent was distilled in vacuo (40 mm) until a residue was obtained. Theresidue was chromatographed (silica, 1:1 hexane/methylene chloride) toafford 2.7 g (61.3%) of 1-(3-furyl)-indene as a clear oil.

(c)

A mixture of 4.28 g (0.014 mol) of benzo[b]quinoliziniumhexafluorophosphate and 2.6 g (0.0143 mol) of 1-(3-furyl)-indene in 75mL of nitromethane was heated to reflux for 2 h, cooled to 0° C.,filtered, and concentrated in vacuo. The brown foamy residue wastriturated in ether, a tan solid product was filtered to afford 6.5 g of6,11[[2',3']-3'-(3-furyl)-indanyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR42## R⁵═3-furanyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR43## R⁶═3-furanyl; X⁻ ═PF₆ ⁻), as a tan solid, m.p.155°-161° C., isomericratio, 1.1:1.

(d)

6,11[[2',3']-3'-(3-Furyl)-indanyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (1.3 g, 0.00256 mol) was converted to thecorresponding chloride salt by passing the hexafluorophosphate adductthrough Dowex® 1×2-200 to afford, after by drying in vacuo for 12 h, 420mg of 6.11[[2',3']-3'-(3-furyl)indanyl]6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR44## R⁵ ═3-furanyl; X⁻═Cl⁻), m.p. 188°-193° C., as a white solid.

EXAMPLE 7 (a)

To a solution of 10.2 mL (0.102 mol) of 10M n-butyllithium in hexane in200 mL of ether cooled to -78° C. was added dropwise 15 g (0.102 mol) of3-bromofuran and the mixture was stirred for 15 min. To the above cooledmixture was added 12.61 g (0.092 mol) of4',5',6',7'-tetrahydrobenzofuran-7-one in 50 mL of THF and the mixturewas allowed to warm to room temperature, and then stirred for 15 min. Tothe mixture was added saturated ammonium chloride solution and theresulting mixture was extracted with ethyl acetate (3×100 mL), and theorganic layer was washed with brine, dried over sodium sulfate andconcentrated in vacuo to afford 16.3 g (86%) of4',5',6',7'-tetrahydro-7-(3-furyl)-benzofuran-7-ol, a red oil.

To a mixture of 16.3 g of the above alcohol in 400 mL of toluene wasadded 100 mg of p-toluenesulfonic acid monohydrate and the mixture wasplaced on a Rotovap and the solvent was distilled in vacuo (40 mm/50°C.) until a brown-red residue was obtained yielding 14.3 g (96%) of4,5-dihydro-7-(3-furyl)-benzofuran as a red oil.

(b)

To a mixture of 19 g (0.062 mol) of benzo[b]quinoliziniumhexafluorophosphate and 200 mg of potassium carbonate in 200 mL ofacetonitrile was added 14.3 g (0.0768 mol) of4,5-dihydro-7-(3-furyl)-benzofuran and the mixture was heated to refluxfor 10 min, cooled, and concentrated in vacuo. The residue wastriturated in ether (300 mL), a brown solid product was filtered anddissolved in 300 mL of isopropanol, heated to 50° C. and cooled. Thesolid was filtered and chromatographed on silica (13%acetonitrile/methylene chloride) to afford 13.8 g of6,11[[5',4']-4'-(3-furyl)-4',5',6',7'-tetrahydrobenzofuryl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR45## R⁵═3-furanyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR46## R⁶═3-furanyl; X⁻ ═PF₆ ⁻), as a tan solid, m.p. 203°-210° C. (1:1.8 mixtureof isomers). The solid was further purified by dissolving in 400 mL ofmethylene chloride/ethanol (1:1) with heating, distilling methylenechloride, followed by cooling to yield the product as an enriched 5.6:1mixture of the geometric isomers.

(c)

6,11-[5',4']-4'-(3-Furyl)-4','5',6',7'-tetrahydrobenzofuryl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, enriched isomer, (1.3 g, 0.00256 mol) was convertedto the corresponding chloride salt by passing the hexafluorophosphatethrough Dowex® 1×2-200 (65 g) after placing the hexafluorophosphate saltwith 10 mL of acetonitrile. The residue obtained was dissolved inacetonitrile, heated to reflux, ethyl acetate was added, cooled andfiltered to afford 2.2 g (70.9%) of6,11-[5',4"]-4'-(3-furyl)-4',5',6',7'-tetrahydrobenzofuryl]-6,11-dihydrobenzo[b]quinoliziniumchloride, Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR47## R⁵ ═3-furanyl; X⁻═Cl⁻) m.p. 253°-256° C., as a tan solid.,

EXAMPLE 8 (a)

To a solution of 4 mL (0.04 mol) of 10M n-butyllithium in hexane cooledto -78° C. was added 3.59 mL (0.04 mol) of 3-bromofuran in 100 mL ofether and the mixture was stirred for 10 min. To the above cooledsolution was added 5.49 g (0.036 mol)4',5',6',7'-tetrahydro-3-methyl-benzisoxazol-7-one and the mixture wasallowed to warm to room temperature, and then stirred for 1 h. To themixture was added saturated ammonium chloride solution and the resultingmixture was extracted with ethyl acetate (3×100 mL), and the organiclayer was washed with brine, dried over sodium sulfate and concentratedin vacuo to afford 7.6 g (96%) of7-(3-furyl)-3-methyl-4',5',6',7-tetrahydrobenzisoxazol-7-ol, as a brownoil.

(b)

To a mixture of 7.6 g (0.034 mol) of7-(3-furyl)-3-methyl-4',5',6',7'-tetrahydrobenzisoxazol-7-ol in 300 mLof toluene was added 100 mg of p-toluenesulfonic acid and the mixturewas placed on a Rotovap, and the solvent was distilled in vacuo (80° C.)until an oil residue was obtained. Toluene (200 mL) was added to theabove residue, the mixture was placed on a Rotovap, and the solvent wasdistilled in vacuo to complete the reaction. The oil was chromatographed(silica, 1:1 hexane/methylene chloride) to afford 3.36 g (95%) of7-(3-furyl)-3-methyl-4,5-dihydrobenzisoxazole, (Formula III: R³ ═H;##STR48## R⁵ ═3-furanyl) as a clear oil.

(c)

A mixture of 3.86 g (0.0124 mol) of benzo[b]quinoliziniumhexafluorophosphate and 3 g (0.0149 mol) of7-(3-furyl)-3-methyl-4,5-dihydrobenzisoxazole in 50 mL of nitromethanewas heated to reflux for 14 h, cooled, and concentrated in vacuo. Theresidue was triturated in ether (100 mL), and a tan solid product wasfiltered. This solid was chromatographed (silica, 9% methanol/methylenechloride) and dried to afford 1.6 g of6,11[[6',7']-7'-(3-furyl)-3'-methyl-4',5',6',7'-tetrahydrobenzisoxazol]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR49## R⁵═3-furanyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR50## R⁶═3-furanyl; X⁻ ═PF₆ ⁻), m.p.150°-156° C., (1:2.29 mixture of isomers).

EXAMPLE 9 (a)

To a solution of 20 g (0.147 mol) of 4,5,6,7-tetrahydrobenzofuryl-4-onewas added 31.8 mL of triethylorthoformate, 34.5 mL of ethanol, and 100mg of p-toluenesulfonic acid monohydrate and the mixture was stirred for16 h. To the above mixture was added 2 g of potassium carbonate, and themixture was stirred for 5 min, filtered and concentrated in vacuo toafford 24.1 g of a 2:1 mixture of 4-ethoxy-6,7-dihydrobenzofuran andstarting 4',5',6',7'-tetrahydro-benzofuryl-4-one.

(b)

A mixture of 5 g (0.0163 mol) of benzo[b]quinoliziniumhexafluorophosphate and 8.5 g (0.0407 mol) of4-ethoxy-6,7-dihydrobenzofuran, and 100 mg of p-toluenesulfonic acidmonohydrate in 100 mL of acetonitrile was heated to reflux for 10 h,cooled, and concentrated in vacuo. The brown residue was triturated inether (30 min), a tan solid product was filtered and chromatographed onsilica (15% acetonitrile/methylene chloride) to afford 3.69 g (46%)of6,11[[5',4!]-4'-ethoxy-4',5',6',7'-tetrahydrobenzofuryl]-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R³ ═R⁷ H; ##STR51## R⁵ ═CH₃ CH₂O; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ H; ##STR52## R⁶ ═CH₃ CH₂ O;X⁻ ═PF₆ ⁻), as a yellow foam, m.p.101°-107° C., (1:1.36 mixture ofisomers).

EXAMPLE 10 (a)

To a solution of 11.1 g (0.0939 mol) of benzofuran in 150 mL of ethercooled to -20° C. was added a solution of 9.39 mL (0.0939 mol) of 10Mn-butyllithium in hexane, and the mixture was heated to warm to 0° C.and stirred for 30 min. The mixture was cooled to -78° C. and 10.6 g(0.078 mol) of 4',5',6',7'-tetrahydrobenzofuran-4-one in 20 mL of etherwas added dropwise and the mixture was heated to warm to roomtemperature, and then stirred for 1 h. To the mixture was addedsaturated ammonium chloride solution and the resulting mixture wasextracted with ethyl acetate (3×100 mL). The organic layer was washedwith brine, dried over sodium sulfate and concentrated in vacuo toafford 19.3 g (97%) of4',5',6',7'-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol, an oil whichcrystallized on standing as a yellow solid.

(b)

To a mixture of 19.3 g of4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 mL of toluenewas added 100 mg of p-toluenesulfonic acid monohydrate, and the mixturewas placed on a Rotovap, and the solvent was distilled in vacuo (60° C.)until a residue was obtained. The residue was chromatographed on silica(hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula Ill: R³ ═H; ##STR53##R⁵ ═2-benzofuryl) as an orange oil.

(c)

To a mixture of 5.5 g (0.0179 mol) of benzo[b]quinoliziniumhexafluorophosphate in 100 mL of acetonitrile was added 5.51 g (0.0768mol) of 6,7-dihydro-4-2-benzofuryl-benzofuran and the mixture was heatedto reflux for 2 h, cooled, and concentrated in vacuo. The residue wastriturated in ether, a tan solid product was filtered andchromatographed on silica (13% acetonitrile/methylene chloride) toafford 16 g of6,11[[5',4']-4'-(2-benzofuryl)-4',5',6',7'-tetrahydrobenzofuryl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Example 10(c): isomeric ratio 1:1.3) as a yellowfoam, m.p. 146°-150° C. Isomeric separation was achieved by dissolvingthe mixture in 400 mL of methanol with heating, followed by cooling, andseparating a solid (methanol insoluble G-isomer) via filtration and amethanol soluble isomer K.

The solid G was fractionally recrystallized from methanol/methylenechloride to afford 2.0 g of6,11[[5',4']-4'-(2-benzofuryl)-4',5',6',7'-tetrahydrobenzofuryl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR54## R⁶═2-benzofuryl; X⁻═PF₆ ⁻ ; Example 10(c)-G), m.p. 238°-242° C., as awhite solid.

The filtrate containing methanol soluble isomer K was concentrated to100 mL, and the insoluble G-isomer was removed. The purificationprocedure of retaining methanol soluble K-isomer and removing themethanol insoluble G-isomer was repeated to afford 1.4 g of6,11[[5',4']-4'-(2-benzofuryl)-4',5',6',7'-tetrahydro-benzofuryl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR55## R⁵═2-benzofuryl; X⁻ ═PF₆ ⁻ ; Example 10(c)-K), m.p.170°-176° C., as apale-yellow solid.

EXAMPLE 11 (a)

To a solution of furan-3-carboxylic acid (26 g, 0.23 mol) in 250 mL oftoluene was added 24.15 mL (0.276 mol) of oxalyl chloride and 1 drop ofpyridine and the mixture was heated on a steam-bath for 2 h. The mixturewas cooled to room temperature, and N,O-dimethylhydroxaminehydrochloride (24.66 g, 0.253 mol), 4-dimethylaminopyridine (DMAP, 1.2g, 0.01 mol), and 600 mL of methylene chloride were added. The mixturewas cooled to 0° C., 50.1 mL of pyridine in 50 mL of methylene chloridewas added slowly, the mixture was heated to warm to room temperature (3h), and 2 g of N,O-dimethyl-hydroxamine hydrochloride and 1 g of4-dimethylaminopyridine (DMAP) were added. The resulting mixture wasstirred for 12 h. The above mixture was cooled to 0° C., filtered, andthe filtrate was washed with 3N HCl, brine, dried over sodium sulfate,and concentrated in vacuo to yield 14 g (39%) of3-(N-methyl-N-methoxycarbamoyl)furan.

(b)

To a solution of 3-(N-methyl-N-methoxycarbamoyl)furan (14 g, 0.09 mol)in 150 mL of THF cooled to -78° C. was added in portions 36.1 mL (0.108mol) of 3M methylmagnesium bromide in ether and the mixture was heatedto warm to room temperature, and then stirred for 30 min. To the abovemixture was added a cold 2N HCl (100 mL) and the aqueous layer wasextracted with ether (3×100 mL), the combined organic layer was washedwith brine, dried over sodium sulfate, and concentrated in vacuo toyield a pale-yellow oil. The above oil was chromatographed on silica(methylene chloride/hexane 2:1) to afford 6.95 g (70.2%) of1-(3-furyl)-1-propanone as a colorless oil which crystallized as a whitesolid.

(c)

To a stirring mixture of 1-(3-furyl)-1-propanone (6.75 g, 0.0612 mol) in150 mL of methylene chloride was added TEOF (13.2 mL, 0.079 mol) withstirring followed by 100 mg of p-toluenesulfonic acid monohydrate andthe resulting mixture was stirred for 126 h. Potassium carbonate (2 g)was added to the above reaction mixture, stirred for 10 min, filtered,and concentrated in vacuo. The residue was distilled (35 mm, 82°-85° C.)to afford 2.5 g (29%) of 1-(3-furyl)-1-ethoxy-ethylene (Formula III: R³═R⁴ ═H; R⁵ ═CH₃ CH₂ O; R⁶ ═3-furanyl), as a clear oil.

(d)

To a mixture of 4.59 g (0.015 mol) of benzo[b]quinoliziumhexafluorophosphate in 50 mL of acetonitrile was added1-(3-furyl)-1-ethoxyethylene (2.5 g, 0.018 mol) and the mixture washeated to reflux for 20 min, cooled, filtered, and concentrated invacuo. The brown residue was triturated in ether for 1 h, a tan solidproduct was filtered and dried in vacuo to yield 6.3 g (90%) of6,11-ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, as a tan solid, m.p.143°-147° C., (1.59:1 mixtureof isomers).

(e) Isomeric Separation

6,11-Ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (6.0 g) was dissolved in hot methanol/isopropanol(1:3) and filtered while hot, separating insoluble solid isomer P andsoluble isomer R.

Isomer P--the solid insoluble in hot methanol/isopropanol (1:3) wasfractionally recrystallized from methanol/isopropanol (1:5), followed bydissolving the solid in methylene chloride/methanol/isopropanol (1:1:4)and distilling methylene chloride to isolate 1.75 g of6,11-ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (isomer P).

Isomer R--the solid soluble in hot methanol/isopropanol (1:3) wassuccessively treated with hot methanol/isopropanol (1:5) to remove theinsoluble solid, while retaining the soluble product and then distillingmethanol to 1/2 of its original volume to yield upon cooling andfiltration 629 mg of6,11-ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (isomer R).

(f)

6,11-Ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (isomer R, 629 mg, 0.00135 mol) was converted to thecorresponding chloride salt by passing the hexafluorophosphate dissolvedin CH₃ CN (5 mL) through Dowex® 1×2-200 (45 g) eluting with H₂ O. Theaqueous fractions were concentrated and the residue obtained was driedin vacuo (0.1 mm/40° C./12 h) to afford 460 mg (95.8%) of6,11-ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumchloride, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═3-furanyl; R⁶ ═CH₃ CH₂O; X⁻ --Cl⁻), m.p. 178°-182° C., as a white solid.

(g)

6,11-Ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (isomer P, 1.75g, 0.0037 mol) was convened to thecorresponding chloride salt by passing the hexafluorophosphate dissolvedin CH₃ CN (10 mL) through Dowex® 1×2-200 (65 g) eluting with H₂ O, andconcentration of residue. The residue obtained was dried in vacuo (0.1mm/40° C./12 h) to afford 1.2 g (90.2%) of6,11-ethano-12-(3-furyl)-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumchloride, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ =H; R⁵ ═CH₃ CH₂ O; R⁶═3-furanyl; X⁻ ═Cl⁻), m.p. 132°-136° C., as an off-white solid.

EXAMPLE 12 (a)

A mixture of (2,5-dimethyl-3-acetyl)-furan (12.5 g, 0.09 mol), 300 mg ofp-toluenesulfonic acid monohydrate, 21.2 mL (0.35 mol) of ethanol, and29.9 mL (0.18 mol) of triethylorthoformate in 250 mL of methylenechloride was stirred at room temperature 72 h, then 1 g of potassiumcarbonate, was added. The mixture was stirred for 5 min, filtered, andconcentrated in vacuo. The residue was distilled (40-45 mm/115°-125° C.)to afford 7.94 g (53.2%) of1-[(2,5-dimethyl)-3-furyl]-1-ethoxy-ethylene, (Formula III: R³ ═R⁴ ═H;R⁵ ═CH₃ CH₂ O; R⁶ ═2,5-dimethyl-3-furanyl); as a clear oil.

(b)

To a mixture of 6 g (0.0196 mol) of benzo[b]quinoliziniumhexafluorophosphate in 100 mL of acetonitrile was added1-[(2,5-dimethyl)-3-furyl]-1-ethoxy-ethylene (3.9 g, 0.0235 mol) and 100mg of p-toluenesulfonic acid monohydrate and the mixture was heated toreflux for 24 h, cooled, filtered, and concentrated in vacuo. The brownresidue was triturated in ether (150 mL) for 1 h, and a tan solidproduct was filtered and dried in vacuo. The solid residue waschromatographed on silica (13% acetonitrile/methylene chloride) toyield, after crystallization from isopropanol,6,11-ethano-12-(2,5-dimethyl)-3-furyl]-12-ethoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═CH₃ CH₂ O; R⁶═2,5-dimethyl-3-furyl; X⁻ ═PF₆ ⁻ and Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H;R⁵ ═2,5-dimethyl-3-furyl; R⁶ ═CH₃ CH₂ O; X⁻ ═PF₆ ⁻) as a tan solid,(1:1.33 mixture of isomers).

EXAMPLE 13 (a)

To a mixture of 8 g of 6-methyl-benzo[b]quinolizinium perchlorate(Bradsher and Parham J. Het. Chem. 1964, 1, 121-124) in 200 mL ofethanol was added 7.86 g (0.057 mol) of 1-(3-furyl)-1-ethoxy-ethyleneand 75 mL of acetonitrile and the mixture was heated to reflux, cooled,filtered (to remove the perchlorate salt) and the solvent was heated toevaporate at room temperature. The residue was triturated in 50 mL ofmethylene chloride, filtered, and the filtrate was concentrated in vacuoand the resulting residue was chromatographed on silica (methylenechloride/ethyl acetate/methanol, 7:2:1 ) to afford 7.5 g of6,11-ethano-12-(3-furyl)-12-ethoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═CH₃ CH₂ O; R₆═3-furyl; X⁻ =ClO₄ ⁻ and Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵═3-furyl; R⁶ ═CH₃ CH₂ O; X⁻ ═ClO₄ ⁻) as a whim solid (isomeric ratio,1:1).

(b)

6,11-Ethano-12-(3-furyl)-12-ethoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate of Example 13(a) (5.4 g), was converted to the correspondingchloride salt by passing the perchlorate through Dowex® 1×2-200 toafford 5.4 g (0.0125 mol) of the chloride salt which was treated with4.955 g (0.0125 mol) of potassium monobenzoyl-D-tartarate in methylenechloride to afford 10.05 g of the monobenzoyl-D-tartarate salt as awhite solid. The monobenzoyl-D-tartarate salt was recrystallized (3x)from ethanol to yield 100 mg of6,11-ethano-12-(3-furyl)-12-ethoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniummonobenzoyl-D-tartarate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵═3-furyl; R⁶ ═CH₃ CH₂ O; X⁻ ═(-)C₁₈ H₁₄ O₈), as a white solid, m.p.150°C.

EXAMPLE 14 (a)

To a solution of 3,3-difurylmethanone (3 g, 0.0185 mol) in 50 mL of THFcooled to 0° C. was added 7.4 mL (0.022 mol) of 3M ethylmagnesiumbromide in ether and the mixture was heated to warm to room temperature,and then stirred for 30 min. To the above mixture was added ammoniumchloride solution, the mixture was extracted with ethyl acetate, and theorganic layer was dried over sodium sulfate and concentrated in vacuo toyield 2.5 g (70.4%) of 1,1-(di-3-furyl)-propanol, a brown oil.

(b)

A mixture of 1,1-(di-3-furyl)-propanol (2.95 g. 0.0153 mol) and 150 mLof p-toluenesulfonic acid monohydrate in toluene was heated to 70° C.and the mixture was distilled to remove toluene in vacuo to yield apale-yellow oil. The above oil was chromatographed on silica(hexane/methylene chloride 3:1) to afford 500 mg (18.7%) of1,1-(di-3-furyl)-2-methyl-ethylene, (Formula III: R³ ═CH₃ ; R⁴ ═H; R⁵═R⁶ ═3-furyl), as a clear oil.

(c)

A mixture of 0.78 g (0.00256 mol) of benzo[b]quinoliziniumhexafluorophosphate and 1,1-(di-3-furyl)-2-methyl-ethylene (0.49 g,0.0028 mol) in 25 mL of nitromethane was heated to reflux for 8 h, and50 mL of methylene chloride was added. The mixture was cooled to 0° C.,filtered, and the filtrate was concentrated in vacuo. The solid residuewas triturated in ether, filtered, and chromatographed on silica (15%acetonitrile/methylene chloride) to afford 150 mg (11%) of6,11-ethano-12,12-difuryl-13-methyl-6,11-dihydrobenzo[b]-quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; R⁴ ═CH₃ ; R⁵ ═R⁶═3-furyl; X⁻ ═PF₆ ⁻ and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; R³ ═CH₃ ; R⁵ ═R⁶═3-furyl; X⁻ ═PF₆ ⁻) as a tan solid, m.p.122°-126° C.

EXAMPLE 15 (a)

To a solution of 7.22 mL (0.0722 mol) of 10M n-butyllithium in hexane in150 mL of ether cooled to -78° C. was added 10.62 g (0.0722 mol) of3-bromofuran and the mixture was stirred for 15 min. To the above cooledmixture was added 10 g (0.0656 mol) of4,5,6,7-tetrahydro-thianaphthen-4-one in 25 mL of THF and the mixturewas heated to warm to room temperature, and then stirred. To the mixturewas added saturated ammonium chloride solution and the resulting mixturewas extracted with ethyl acetate (3×100 mL), and the organic layer waswashed with brine, dried over sodium sulfate and concentrated in vacuoto afford 13.6 g (94.2%) of4-(3-furyl)-4,5,6,7-tetrahydro-thianaphthen-4-ol, as a brown oil.

(b)

To a mixture of 13.6 g (0.0618 mol) of4-(3-furyl)-4,5,6,7-tetrahydrothianaphthen-4-ol in 250 mL of toluene wasadded 600 mg of p-toluenesulfonic acid monohydrate. The mixture wasplaced on a Rotovap and toluene was distilled in vacuo (60° C.) until aresidue was obtained. The residue was chromatographed (silica, 3:1hexane/methylene chloride) to afford 11.6 g (92.9%) of4-(3-furyl)-6,7-dihydrothianaphthene as a pale-yellow oil.

(c)

A mixture of 6 g (0.0196 mol) of benzo[b]quinoliziniumhexafluorophosphate and 5.12 g (0.023 mol) of4-(3-furyl)-6,7-dihydrothianaphthene in 100 mL of nitromethane washeated to reflux for 14 h, cooled, and concentrated in vacuo. Theresidue was dissolved in ethyl acetate (200 mL), filtered, and thefiltrate was concentrated in vacuo, the residue was dissolved in ether,and the ether solution was cooled to yield 11 g of6,11[5',']-4'-(3-furyl)-4',5',6',7'-tetrahydrothianaphthyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate as a gray solid, (1:1.03 mixture of isomers). Thegray solid, product was dissolved in 500 mL of isopropanol/methylenechloride (3:2) on a steam-bath while distilling 150 mL of methylenechloride and cooled to afford6,11[[5',4']-4'-(3-furyl)-4',5',6',7'-tetrahydrothianaphthyl]6,11]-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; ##STR56## R⁵═3-furyl; X⁻ ═PF₆ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR57## R⁶═3-furyl; X-═PF₆ ⁻), as a tan solid (1:1 mixture of isomers).

EXAMPLE 16 (a)

A mixture of 0.52 g of benzo[b]quinolizinium bromide and 1.02 g of1,1-diphenylethylene in 50 mL of nitromethane was heated to reflux underargon for 16 h, cooled, and concentrated in vacuo. The residue waschromatographed on silica (methylene chloride/methanol 9:1), the solidproduct was dissolved in 50 mL of warm water, filtered, and thefiltrated was treated with 10% sodium perchlorate solution. The solidprecipitate was filtered, washed with hexane, ether, and dried in vacuofor 72 h to afford6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═phenyl; X⁻ ═ClO₄⁻), m.p.150° C. (d).

EXAMPLE 17 (a)

A mixture of 4.6 g (0.0165 mol) of benzo[b]quinolizinium perchlorate and9 g of 1,1-diphenylethylene (0.05 mol) in 250 mL of nitromethane washeated to reflux under nitrogen for 16 h. The reaction mixture waspoured into 100 mL of water, shaken, and the organic layer was separatedand washed with 100 mL of water, and the nitromethane layer wasconcentrated in vacuo to 50 mL of its volume. To the above nitromethanelayer was added 100 mL of water, the resulting mixture was concentratedin vacuo, and the residue was dissolved in 200 mL of acetonitrile and500 mL of water. The above mixture was extracted with hexane (3×100 mL;a black oil insoluble in both hexane and acetonitrile/water wasremoved), and the aqueous layer was steam distilled to removeacetonitrile to yield an oil which crystallized on standing. The solidproduct was washed with 200 mL of ether, 200 mL of hexane, and 200 mL ofether to afford 5.1 g (67%) of6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, as a tan solid.

(b)

A Dowex® column was prepared with 150 g of Dowex® 1×2-200 in 0.5N HCl,washed with 0.5N HCl, followed by water until the pH was 4-5.6,11-Ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinolizinium perchlorate(5.1 g) was dissolved in 40 mL of acetonitrile and was placed on thecolumn, eluted with water, and the aqueous eluent was concentrated invacuo (45° C.). The residue was dissolved in 50 mL of warm acetonitrile,treated with activated charcoal, filtered through diatomaceous earth,and the filtrate triturated in isopropyl acetate to yield an insolublesolid (0.5 g). The above filtrate (isopropyl acetate) was concentrated,the residue was triturated in acetonitrile, and filtered to yield 1.6 gof an amorphous solid. The mother liquor (acetonitrile) was concentratedfurther to obtain 2.0 g of an amorphous solid. All solid products werecombined and dried in vacuo (48 h) to give 4.036 g of a white solidwhich was recrystallized from 100 mL of water and dried in vacuo toafford 3.57 g of6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinolizinium chloride,(Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═phenyl; X⁻ ═Cl⁻), as a whitesolid, m.p. 169°-174° C.

EXAMPLE 18 (a)

A mixture of 0.5 g of benzo[b]quinolizinium perchlorate and 1 g of1,1-diphenyl-2-methyl-ethylene in 40 mL of nitropropane was heated toreflux under nitrogen for 2 h. An additional1,1-diphenyl-2-methyl-ethylene (0.3 g) was added and the mixture wasrefluxed for 48 h. The reaction mixture was concentrated in vacuo, theresidue was triturated in ether/hexane (1:1), and the solid wasfiltered. The above solid was resuspended with methylene chloride/hexane(1:1), and filtered. The filtrate was concentrated in vacuo, and theresulting residue was chromatographed on silica (methylene chloride andthen methylene chloride/methanol 9:1) to afford 0.52 g of6,11-ethano-12,12-diphenyl-13-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, as a foamy solid.

The above perchlorate was purified by dissolving the solid inmethanol/ethyl acetate (9:1), treating the solution with activatedcharcoal, and concentrating the filtrate in vacuo to yield a foamysolid. The purified solid was convened to the corresponding chloridesalt by passing the perchlorate through Dowex® 1×2-200 exchange resin.The chloride salt residue obtained was dissolved in 10 mL of methanol,treated with 10% sodium perchorate solution (10 mL), stirred for 10 min,and methanol was removed in vacuo to yield a solid product. The aboveperchlorate salt was washed with water, ether, and hexane and dried invacuo to afford 0.12 g of6,11-ethanol-12,12-diphenyl-13-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, (Formula I: R¹ ═R² ═R³ ═R⁷ ═H; R⁴ ═CH₃ ; R⁵ ═R⁶ ═phenyl; X⁻═ClO₄ ⁻ ; and Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; R³ ═CH₃ ; R⁵ ═R⁶ ═phenyl; X⁻═ClO₄ ⁻), m.p. 197°-199° C.

EXAMPLE 19 (a)

A mixture of 0.52 g of 6-methylbenzo[b]quinolizinium perchlorate and1.02 g of 1,1-diphenylethylene in 40 mL of nitromethane was heated toreflux under nitrogen for 16 h. An additional 1,1-diphenylethylene (0.5g) was added, and the mixture was refluxed for an additional 72 h,cooled, and concentrated. The residue was triturated in hexane/ether(1:1), filtered, dried, and chromatographed on silica (methylenechloride/methanol 9:1) to afford 0.88 g of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate as a solid.

(b)

6,11-Ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (850 mg) was converted to the corresponding chloride salt bypassing the perchlorate through 100 g of Dowex® 1×2-200 exchange resinto afford 580 mg (79.4%) of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydro-benzo[b]quinolizinium.Chloride, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═phenyl; X⁻═Cl⁻) as a solid, m.p. 160° C. (d).

EXAMPLE 20 (a)

A mixture of 1-(1-methyl-benzyl)2-(1,3-dioxolan-2-yl)pyridiniumperchlorate (18 g) and 100 g of polyphosphoric acid was heated to heatat 100° C. for 5 h and then the mixture was allow to stand at roomtemperature overnight. To the mixture was added 200 mL of water, thereaction mixture was stirred for 30 min, filtered, and sodiumperchlorate solution (a slight excess) was added to the above filtrate.The precipitated solid was filtered and dried to afford 10.5 g (70%) of(6-methyl-benzo[b]quinolizinium perchlorate (Formula II: R¹ ═R⁷ ═H; R²═CH₃ ; X⁻ ═ClO₄ ⁻) as a yellow solid.

(b)

A mixture of 9.5 g (0.032 mol) of 6-methyl-benzo[b]quinoliziniumperchlorate and 16.2 g (0.09 mol) of 1,1-diphenylethylene in 100 mL ofnitromethane was heated to reflux for 3 days. The reaction mixture wasfiltered through a pad of silica gel, washed with 150 mL ofacetonitrile, the filtrate was triturated with ether, and thecrystalline white solid was filtered, washed with ether, and dried toafford 18.3 g (100%) of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R.sup. 50 R⁶-phenyl; X⁻ ═ClO₄ ⁻) as a white solid.

(c)

To a solution of dibenzoyl-L-tartrate (64 g, 0.17 mol) in 450 mL ofmethanol was added dropwise a solution of potassium hydrogen carbonate(17.2 g, 0.17 mol) in 100 mL of water in 4 min and the mixture wasstirred overnight. The white solid formed was filtered, washed with 100mL of methanol, dried in an oven in vacuo to afford 67.4 g (86.5%) ofmono-potassium monobenzoyl-L-tartarate.

(d)

A mixture of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (15.8 g, 0.033 mol) and mono-potassiummonobenzoyl-L-tartarate (13.2 g, 0.033 mol) in 2 L of methanol wasgently warmed on a steam bath to dissolve the solids, and then filtered.The filtrate was concentrated, the residue was combined with 2 L ofmethylene chloride with stirring, and re-filtered to remove potassiumperchlorate. The methylene chloride filtrate on standing at roomtemperature yielded a white solid which was recrystallized frommethylene chloride/methanol to afford 5.7 g of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniummonobenzoyl-L-tartarate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶═phenyl; X⁻ ═[(-)-DBT]) as a white solid, m.p. 160°-161° C.

(e)

The mother liquor from the above recrystallization (methylenechloride/methanol) containing 6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinolizinium perchloratewas passed through 100 g of Dowex® 1×2-200. The residue obtained wasdissolved in 4 L warm water/methanol (1:1), the solution was stirred, 14g of sodium perchlorate in 100 mL of water was added, methanol wasremoved in vacuo, and a crystalline solid was filtered and washed withwater.

The above solid was dissolved in 75 mL of methylene chloride, thesolution was extracted with 50 mL of water containing 1 g of sodiumperchlorate, and washed with water. The organic layer was concentratedin vacuo, the residue was flash chromatographed on silica (methylenechloride/acetonitrile to afford 8.7 g of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate, as an amorphous solid.

(f)

To a solution of dibenzoyl-D-tartarate (49.2 g, 0.1307 mol) in 345 mL ofmethanol was added dropwise a solution of potassium hydrogen carbonate(13.09 g, 0.1307 mol) in 77 mL of water in 4 min and the mixture wasstirred overnight. The white solid formed was filtered, washed with 100mL of methanol, dried in vacuo to afford 51.6 g (84%) of mono-potassiummonobenzyyl-D-tartarate.

(g)

A mixture of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (8.5 g, 0.0179 mol) and mono-potassiummonobenzoyl-D-tartarate (7.11 g, 0.0179 mol) in 1 L of methanol wasgently warmed on a steam bath to dissolve the solids, the mixture wasconcentrated, the residue was dissolved in 500 mL of methylene chloridewith stirring, and filtered to remove potassium perchlorate. Themethylene chloride filtrate was concentrated to 200 mL of its volume,cooled, filtered, and the solid obtained was washed with methylenechloride (2×20 mL) to afford 6.8 g (51.9%) of 6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniummonobenzoyl-D-tartarate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶═phenyl; X⁻ ═[(+)-DBT]), as a white solid, m.p. 160°-161° C.

(h)

6,11-Ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniummonobenzoyl-D-tartarate (6.8 g) was passed through Dowex® 1×2-200 (100g). The residue obtained was dried in vacuo to afford 3.84 g of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumchloride 1/2 hydrate, (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶═phenyl; X⁻ ═Cl⁻ ; as (-)-isomer), as an amorphous solid, [α]_(D) ²⁵=-50.7° in CHCl₃, C=10 mg/mL.

EXAMPLE 21

6,11-Ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniummonobenzoyl-L-tartarate (11 g) was converted to the correspondingchloride salt by passing the mono benzoyl-L-tartrate through Dowex®1×2-200 (100 g) after placing the salt in 50 mL of methanol. Theamorphous residue obtained was dried in vacuo to afford 2.7 g of6,11-ethano-12,12-diphenyl-6-methyl-6,11-dihydrobenzo[b]quinoliziniumchloride hydrate (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶═phenyl; X⁻ ═Cl⁻ ; as (+)-isomer) as a solid, [α]_(D) ²⁵ =+50.9° inCHCl₃, C=10 mg/mL.

EXAMPLE 22 (a)

A mixture of 1.0 g of benzo[b]quinolizinium perchlorate and 1.28 g of1,1-diphenylmethylenecyclopropane in 40 mL of nitromethane was heated toreflux under nitrogen for 16 h. The mixture was concentrated in vacuoand the residue was triturated in hexane/ether (1:1), filtered, dried,and chromatographed on silica (methylene chloride/methanol 9:1 ) toafford 2.4 g of6,11-ethano-12,12-diphenyl-13,13-spirocyclopropyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate as a solid.

(b)

6,11-Ethano-12,12-diphenyl-13,13-spirocyclopropyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (2.4 g) was converted to the corresponding chloride salt bypassing the perchlorate through Dowex® 1×2-200 ion exchange resin toafford 2.7 g of6,11-ethano-12,12-diphenyl-13,13-spirocyclopropyl-6,11-dihydrobenzo[b]quinoliziniumchloride, (Formula I: R¹ ═R² ═R⁷ ═H; R³ and R⁴ together form acyclopropyl ring; R⁵ ═R⁶ ═phenyl; X⁻ ═Cl⁻), as a solid.

EXAMPLE 23 (a)

To a solution of bromobenzene (100 g, 0.63 mol) in 300 mL ofdichloroethane cooled to 0° C. was added 169.6 g (1.27 mol) of aluminumchloride. The mixture was stirred (1 min), and 37.6 g (0.378 mol) of1,1,1-trichloroethane in 50 mL of dichloroethene was added and stirredat 0° C. for 1 h. The above mixture was diluted with 500 g of ice,basified with 30% sodium hydroxide solution, filtered, the aqueous layerwas extracted with methylene chloride (2×500 mL), and the combinedorganic layer was dried over sodium sulfate and concentrated in vacuo toyield a brown oil. The brown oil was crystallized from hexane (2×150 mL)to afford 10.5 g of 1,1-di(4-bromo)phenylethylene (Formula III: R³ ═R⁴═H; R⁵ ═R⁶ ═4-bromophenyl) as a white solid. The mother liquor wasconcentrated in vacuo and chromatographed on silica (hexane) to yield18.5 g (total 29 g, 27%) of an additional white solid.

(b)

A mixture of 3.0 g (0.0098 mol) of benzo[b]quinoliziniumhexafluorophosphate and 4.9 g (0.0147 mol) of1,1-di-p-bromophenylethylene in 50 mL of nitromethane was heated toreflux for 8 h. After adding 0.5 g of 1,1-di-p-bromophenylethylene, themixture was refluxed for an additional 12 h. The mixture was cooled,concentrated in vacuo and the residue was triturated in hexane/ether(1:1), filtered, and dried to afford 6.25 g (99.2%) of6,11-ethano-12,12-di-p-bromophenyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═4-bromophenyl; X⁻ ═PF₆ ⁻) as a white solid.

(c)

6,11-Ethano-12,12-di-p-bromophenyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (6.2 g, 0.0096 mol)) was converted to thecorresponding chloride salt by passing the salt through Dowex® 1×2-200(80 g) by placing the salt in 20 mL of acetonitrile. The eluent wasconcentrated in vacuo, and the residue obtained was dried by dissolvingin 200 mL of toluene and concentrating the solution. The resultingresidue was crystallized from ethyl acetate to afford 4.4 g (83%) of6,11-ethano-12,12-di-p-bromophenyl-6,11-dihydrobenzo[b]quinoliziniumchloride, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4-bromophenyl; X⁻═Cl⁻), as a white solid.

EXAMPLE 24 (a)

A mixture of 0.5 g of benzo[b]quinolizinium perchlorate and 0.77 g of1,1-di-(2-pyridyl)ethylene in 30 mL of nitromethane was heated undernitrogen at 100° C. for 8 h. The mixture was cooled, concentrated invacuo, the dark residue was dissolved in 100 mL of methanol, treatedwith activated charcoal, filtered, and concentrated in vacuo to afford0.55 g (62.5%) of6,11-ethano-12,12-di-(2-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-pyridyl; X⁻═ClO₄ ⁻), as a brown foamy solid.

(b)

6,11-Ethano-12,12-di-(2-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (730 mg) was purified by passing through a pad of silica gel(dichloromethane/methanol) to yield 4:50 mg of the perchlorate, and theperchlorate was converted to the corresponding chloride salt by passingthe salt through Dowex® 1×2-200 ion exchange resin. The eluent wasconcentrated in vacuo, and the residue obtained was dried to afford 250mg (40%) of6,11-ethano-12,12-di-(2-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumchloride hydrate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-pyridyl;X⁻ ═Cl⁻), as a pale-yellow solid.

EXAMPLE 25 (a)

To a mixture of 63.35 g (0.46 mol) of m-methoxybenzyl alcohol in 1.5 Lof ether cooled to -40° C. was added in 2 portions (100 mL, 1.0 mol) 10Mof n-butyllithium over a 30 min period and the reaction mixture wasslowly (removing a bath) warmed to room temperature by removal of thecooling bath and stirred for 30 minutes. The above reaction mixture wascooled to -20° C., 69.7 g (0.651 mol) of 4-pyridinecarboxaldehyde wasadded to the mixture, and the resulting reaction mixture was heated towarm to room temperature. After 1 h, ammonium chloride solution wasadded to the mixture. The diol was extracted with ethyl acetate, driedover sodium sulfate, and the solvent was removed in vacuo.Recrystallization (2×) from ethyl acetate/ether afforded 68.5 g (60.7%)of 2-[1-hydroxy-(2'-methoxy-6'-hydroxymethyl)-benzyl]pyridine (FormulaX: R¹ ═R² ═H; R⁷ ═6'--OCH₃).

(b)

To 25 g (0.102 mol) of2-[1-hydroxy-(2'-methoxy-6'-hydroxymethyl)benzyl]-pyridine was addedrapidly with stirring 30 mL of POCl₃ and the resulting mixture wasplaced in an oil bath preheated to 110° C. The exothermic reactionmixture (with evolution of HCl gas) was cooled, 2:50 mL of methylenechloride was added, and the solvent was decanted to yield an oil. Theoil was dissolved in water, treated with 5 g of sodium perchlorate, in100 mL of water and the precipitated perchlorate was isolated byfiltration. The above decanted organic solvent was concentrated, theresidual chloride was triturated with 100 mL of methylene chloride, andthe precipitated solid was filtered and converted to the perchlorate bytreating with sodium perchlorate solution. The combined perchloratesalts were crystallized from methanol to afford 12.2 g (38.7%) of10-methoxybenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═10--OCH₃ ; X⁻ ═ClO₄ ⁻).

(c)

A mixture of 5 g (0.016 mol)) of 10-methoxybenzo[b]quinoliziniumperchlorate and 3.49 g (0.0194 mol) of 1,1-di-phenylethylene in 100 mLof nitromethane was heated to reflux for 14 h. The mixture was cooled,filtered, and the filtrate was concentrated in vacuo. The residue wasdissolved in methanol, and filtered to afford 7.29 g (92.2%) of6,11-ethano-12,12-diphenyl-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁷ ═10--OCH₃ ; X⁻ ═ClO₄ ⁻),as a white solid, m.p. 227°-230° C.

EXAMPLE 26

6,11-Ethano-12,12-diphenyl-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (0.0143 mol) was convened to the corresponding chloride saltby passing the salt dissolved in CH₃ CN (20 mL) through Dowex® 1×2-200ion exchange resin (70 g) elutate with H₂ O. The eluent was concentratedin vacuo, and the residue obtained was dried by dissolving in tolueneand distilling the solvent followed by triturating with ethyl acetate toafford 4.4 g (72.3%) of6,11-ethano-12,12-diphenyl-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁷ ═10--OCH₃ ; X⁻ ═Cl⁻), as awhite amorphous solid m.p. 158°-164 ° C.

EXAMPLE 27 (a)

A mixture of pyridine-2-carboxaldehyde (151 g, 1.41 mol), ethyleneglycol (157 mL), and 56 g (0.29 mol) of p-toluenesulfonic acidmonohydrate in 1.4 L of toluene placed in a 5 L flask fitted with a DeanStark trap was heated to reflux for 16 h, removing 50 mL of water. Themixture was concentrated in vacuo to a 800 mL volume, cooled, saturatedsodium hydrogen carbonate solution was added (to pH 8-9), the layerswere separated and the aqueous layer was washed with 100 mL of toluene.The combined organic layer was dried over magnesium sulfate,concentrated in vacuo, and distilled (with a short distilling head) toafford 119.5 g of 2-(1,3-dioxolan-2-yl)-pyridine (Formula V: R¹ ═H) as apale oil, b.p. 100° C./1 mm.

(b)

A mixture of 20 g of 2-(1,3-dioxolan-2-yl)-pyridine and p-methoxybenzylchloride (21.2 g) was stirred at room temperature overnight, then leftto stand six days. The mixture was dissolved in 100 mL of water andextracted with 30 mL ether/hexane (1:1). To the aqueous solution wasadded a solution of potassium hexafluorophophate (excess) in 250 mL ofwater. The solid product precipitate was filtered and dried (2 days) toafford 67g of 1-(p-methoxybenzyl)-2-(1,3-dioxolan-2-yl)pyridiniumhrxafluorophosphate (Formula VII: R¹ ═R² ═H; R⁷ ═4--CH₃ O; X⁻ ═PF₆ ⁻).

(c)

To a mixture of 50 g of polyphosphoric acid and 125 mL ofmethanesulfonic acid heated to 40° C. was added with stirring 52 g(0.125 mol) of 1-(p-methoxybenzyl)-2(1,3-dioxolan-2-yl)pyridiniumhexafluorophosphate and the resulting reaction mixture was heated at105° C. with stirring for 2 hours. The mixture was cooled to roomtemperature and poured into 2 L of ice-water. To the resulting solutionwas added 55 g of potassium hexafluorophosphate with stirring, the solidprecipitate was filtered and dried to afford 56.2 g of9-methoxy-benzo[b]quinolizinium hexafluorophosphate (Formula II: R¹ ═R²═H; R⁷ ═9≧OCH₃ ; X⁻ ═PF₆ ⁻).

(d)

A mixture of 5.82 g (0.0165 mol) of 9-methoxybenzo[b]quinoliziniumhexafluorophosphate and 9 g (0.05 mol) of 1,1-diphenylethylene in 250 mLof nitromethane was heated at reflux overnight. An additional1,1-diphenylethylene (5 g) was added and the mixture was heated for anadditional 72 h, cooled, and 200 mL of water was added with stirring.The organic layer was washed with 100 mL of water and concentrated at55° C. The residue was triturated in a mixture of 200 mL of water, 150mL of acetonitrile, and 50 mL of hexane. The aqueous layer was extractedwith 50 mL of ether, and concentrated in vacuo to afford 4 g of6,11-ethano-12,12-diphenyl-9-methoxy-6,11-dihydro-benzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁷ ═9--CH₃ O; R⁵ ═R⁶═phenyl; X⁻ ═PF₆ ⁻) as a solid.

(e)

6,11 -Ethano-12,12-diphenyl-9-methoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (4 g) was converted to the corresponding chloridesalt by passing the above salt through Dowex® 1×2-200 (150 g) afterplacing the salt in acetonitrile (15 mL). The residue obtained was driedin vacuo to afford 0.97 g of6,11-ethano-12,12-diphenyl-9-methoxy-6,111-dihydrobenzo[b]quinoliziniumchloride 1/2 hydrate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷═9--CH₃ O; X⁻ ═Cl⁻) as a solid.

EXAMPLE 28 (a)

A mixture of 4 g of 10-methoxybenzo[b]quinolizinium perchlorate in 50 mLof 48% HBr was heated at 100° C. for 20 h, cooled to room temperature,and the resulting mixture was poured into 100 mL of 50% sodiumperchlorate solution and stirred for 5 min. The precipitate wasfiltered, washed with ice-water, ether, ethyl acetate and air dried toafford 2.9 g of 10-hydroxybenzo[b]quinolizinium perchlorate, (FormulaII: R¹ ═R² ═H; R⁷ ═10--OH; X⁻ ═ClO₄ ⁻) m.p. 218°-229° C. (d).

(b)

A mixture of 1.4 g (4.7 mmol) of 10-hydroxybenzo[b]quinoliziniumperchlorate and 1.28 g (7.1 mmol) of 1,1-diphenylethylene in 50 mL ofnitromethane was heated to heat at 100° C. for 15 h, cooled to roomtemperature, and the resulting mixture was concentrated in vacuo. Theabove residue was purified by chromatography on silica (methylenedichloride/methanol 9:1) to yield a yellow foamy solid which wastriturated with isopropanol to afford, after filtration, 1.7 g (75.5%)of6,11-ethano-12,12-diphenyl-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═10--OH;X⁻ ═ClO₄ ⁻) as a solid.

(c)

6,11-Ethano-12,12-diphenyl-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.7 g) was converted to the corresponding chloride salt bypassing the above salt through Dowex® 1×2-200 (100 g) to afford 1.28 g(87%) of6,11-ethano-12,12-diphenyl-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═10--OH; X⁻═Cl⁻) as a solid, m.p. >260° C. (d).

EXAMPLE 29 (a)

To a solution of 1,1-di(N-methylsulfonylaminophenyl)ketone (10 g, 0.027mol) in 200 mL of DMF was added 2.6 g (0.065 mol) of 60% NaH dispersion,and the mixture was stirred at room temperature under nitrogen for 1 h,and then p-methoxybenzyl chloride (9.34 g, 0.057 mol) andn-tetra-n-butylammonium bromide (870 mg) were added. The resultingmixture was stirred for 1 h at room temperature, heated at 100° C. undernitrogen for 2 h, cooled to room temperature and poured into 600 mL ofwater. The solid mixture was stirred, 1N HCl solution was added, and theproduct was filtered, washed with water, hexane, ether, and dried toafford 16 g (96.9%) of1,1-di[4-(N-p-methoxybenzyl-N-methylsulfonylamino)phenyl]ketone, as asolid.

(b)

To a suspension of methyl triphenylphosphonium bromide (2.2 g; 6.1 mmol)in 50 mL of DME, was added at room temperature n-butyllithium in hexane(3.8 mL; 6.1 mmol) and the mixture was stirred for 30 min. To the abovereaction mixture was added 3.0 g (4.9 mmol) of1,1-di[4-(N-p-methoxybenzyl-N-methylsulfonylamino)phenyl]ketone in 40 mLof DME/DMPU (2:1), and the mixture was stirred at room temperature for30 minutes and then was heated to reflux under nitrogen for 2 h. Themixture was poured into 250 mL of water, the solid product was filtered,and washed with water and ether respectively, and purified bychromatography on silica eluting with hexane/ethyl acetate (1:1) toafford 1.4 g (46.6%) of1,1-di[4-(N-p-methoxybenzyl-N-methylsulfonyl-amino)phenyl]ethylene(Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═4-[N(SO₂ CH₃)(4-CH₃ Obenzyl)]phenyl) asa solid.

(c)

A reaction mixture containing benzo[b]quinolizinium perchlorate (1.45 g;5.18 mmol) and 1,1-di[4-(N-p-methoxybenzyl-N-methylsulfonylamino)phenyl]ethylene (3 g; 4.94 mmol) in 100 mL of nitromethane was heated toreflux under nitrogen for 24 h. The reaction mixture was cooled,concentrated in vacuo, and the residue was purified by chromatography onsilica eluting with methylene chloride/methanol (9:1). The perchloratewas treated with warm acetonitrile (200 mL), filtered, and the filtratewas concentrated in vacuo to afford 2.0 g (45%) of6,11-ethano-12,12-di[4-(N-p-methoxybenzyl-N-methylsulfonylamino)phenyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate 1/2 ethyl acetate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═4-[N(SO₂ CH₃)(4-CH₃ Obenzyl)]phenyl; X⁻ ═ClO₄ ⁻), m.p. 174°-77° C.

EXAMPLE 30 (a)

To a suspension of methyl triphenylphosphonium bromide (17.83 g; 49.9mmol) in 150 mL of ether was added at -10° 10M n-butyllithium in hexane(4.99 mL; 49.4 mmol) and the mixture was stirred at room temperature for1 h. To the above mixture was added 10 g (47 mmol) of1,1-di(p-tolyl)ketone in 50 mL of ether/tetrahydrofuran (3:2), and themixture was heated to reflux for 2 h, cooled, 20 mL of THF added, andfiltered. To the filtrate was added ammonium chloride solution and theresulting mixture was extracted with ethyl acetate (2×), dried oversodium sulfate and concentrated in vacuo to yield a yellow oil. The oilwas purified through flash chromatography on silica (hexane/methylenechloride 3:1) to afford 9.3 g (95.1%) of 1,1-di(p-tolyl)ethylene(Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═4--CH₃ phenyl).

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(3.5 g; 11.4 mmol) and 1,1-di(p-tolyl)ethylene (2.85 g; 13.7 mmol) in 50mL of nitromethane was heated to reflux under nitrogen for 5 h. Thereaction mixture was cooled, filtered, and the filtrate was concentratedin vacuo to yield a brown foamy solid. The solid product was trituratedwith ether, filtered, and dried to yield 5.8 g (95.4%) of6,11-ethano-12,12-di(p-tolyl)-6,11-dihydrobenzo[b]quinoliziniliumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4--CH₃phenyl; X⁻ ═PF₆ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(p-tolyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (5.8g: 10.8 mmol) was converted to the correspondingchloride salt by passing the hexafluorophosphate salt through Dowex®1×2-200 (60 g) eluting with H₂ O to afford 4.18 g (91.6%) of6,11-ethano-12,12-di-(p-methylphenyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4--CH₃ phenyl; X⁻═Cl⁻), as an off-white solid m.p. 180°-85° C.

EXAMPLE 31 (a)

To a suspension of methyl triphenylphosphonium bromide (42.94 g; 120mmol) in 500 mL of ether was added at -30° C. 10M n-butyllithium inhexane (12.02 mL; 120 mmol) and the mixture was stirred at roomtemperature for 1 h. To the above mixture was added 25 g (114.5 mmol) of1,1-di(p-fluorophenyl)ketone in 100 mL of THF during a 5 min period, andthe mixture was heated to reflux for 2 h, cooled, and filtered. To thefiltrate was added ammonium chloride solution and the resulting mixturewas extracted with ethyl acetate (2×), dried over sodium sulfate andconcentrated in vacuo to yield a red oil which was purified throughflash chromatography on silica (hexane/methylene chloride 5:1) to afford21.2 g (85.7%) of 1,1-di(p-fluorophenyl)ethylene (Formula III: R³ ═R⁴═H; R⁵ ═R⁶ ═4-F-phenyl).

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(3 g, 9.8 mmol) and 1,1-di(p-fluorophenyl)ethylene (3.17 g; 14.7 mmol)in 50 mL of nitromethane was heated to reflux under nitrogen for 6hours. The reaction mixture was cooled, filtered, and the filtrate wasconcentrated in vacuo to yield a foamy solid. The solid product wastriturated with ether, filtered, and dried to yield 5.07 g (87.4%) of6,11-ethano-12,12-di(p-fluorophenyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═4-F-phenyl; X⁻ ═PF₆ ⁻), as a solid.

(c)

6,11-Ethano-12,12-di(p-fluorophenyl)-6,11-dihydrobenzo[b]quinoliniumhexafluorophosphate (5 g: 8.4 mmol) was converted to the correspondingchloride by passing through Dowex® 1×2-200 (60 g) to afford 2.84 g(77.3%) of6,11-ethano-12,12-di(p-fluorophenyl)-6,11-dihydrobenzo[b]-quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4-F-phenyl; X⁻═Cl⁻), m.p. 155°-161° C.

EXAMPLE 32 (a)

A mixture of isopropyl bromide (36.8 mL, 0.39 mol),m-hydroxybenzaldehyde (40 g, 0.327 mol), and potassium carbonate (53.9g, 0.39 mol) in 200 mL of DMF was stirred at room temperature for 12 h.After adding additional isopropyl bromide (20 mL) and potassiumcarbonate (10 g), the reaction mixture was stirred at room temperaturefor 18 h and then heated at 50° C. for 1 h. Water (500 mL) was added tothe mixture, the red oil formed was removed by decantation, and theaqueous layer was extracted with methylene chloride (3×250 mL) and thecombined organic layers were washed with 200 mL of 2N NaOH solution,brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was distilled (0.75 mm/80°-100° C.) to afford 44.2 g (82%)of m-isopropoxybenzaldehyde as a colorless oil.

(b)

To m-isopropoxybenzaldehyde (38 g, 0.23 mol) in 500 mL of ethanol wasadded slowly sodium borohydride (12.2 g, 0.32 mol) over a period of 1 hand the mixture was stirred for 2 h, filtered, and concentrated to 100mL of its volume. The above mixture was diluted with 50 mL of water,neutralized with sulfuric acid solution with cooling, and was extractedwith ether (4×100 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to afford 36.32 g (95%) ofm-isopropoxybenzyl alcohol.

(c)

To a mixture of 30 g (0.18 mol) of 3-isopropoxybenzyl alcohol in 600 mLof ether cooled to -20° C. was added in portions 38.7 mL (0.387 mol) ofn-butyllithium (10M) in hexane over a 20 min period, and the reactionmixture was heated to warm to room temperature and stirred for 2 h. Theabove reaction mixture was cooled to -20° C., 23.13 g (0.216 mol) ofpyridine-2-carboxaldehyde was added in one portion to the mixture, andthe resulting reaction mixture was heated to warm to room temperatureand stirred for 1 h. Ammonium chloride solution (200 mL) and 100 mL ofethyl acetate were added to the mixture. The aqueous layer was extractedwith methylene chloride (2×200 mL), the combined organic layer waswashed with brine, dried over sodium sulfate, and concentrated. The diolwas purified by chromatography on silica eluting with ethylacetate/hexane (9:1; and 0.05% TEA). The solvent was concentrated invacuo, the brown oil was dissolved in methylene chloride/hexane, andremoval of methylene chloride in vacuo to 1/2 of its volume afforded11.1 g (22.6%) of2-[1-hydroxy-(6'-hydroxymethyl-2'-isopropoxy)benzyl]pyridine (Formula X:R¹ ═R² ═H; R⁷ ═2'--OCH(CH₃)₂), as a tan solid.

(d)

To 11.1 g (0.0406 mol) of2-[1-hydroxy-(6'-hydroxymethyl-2'-isopropoxy)benzyl]pyridine was added25 mL of POCl₃ in 1 min, the mixture was heated at 110° C. for 5 min andthen cooled. The reaction mixture was concentrated in vacuo, 100 mL oftoluene was added and concentrated to yield an oil. Water and sodiumperchlorate were added to the above oil, water was decanted, and theresidue was dried under reduced pressure to yield a foam. The foam wasdissolved in methanol/water, potassium hexafluorophosphate was added,and the mixture was heated on a steam-bath and then cooled. The aqueousmixture was concentrated in vacuo, the residue was dissolved inmethylene chloride/methanol, cooled and filtered to remove potassiumperchlorate. The mixture was concentrated in vacuo to 10 mL of itsvolume, ethyl acetate was added and the mixture was cooled. The productwas filtered to afford 5.32 g (34.3%) of 10-isopropoxy-benzo[bquinolizinium hexafluorophosphate (Formula II: R¹ ═R² ═H; R⁷═10--OCH(CH₃)₂ ; X⁻ ═PF₆ ⁻), as an orange solid.

(e)

A reaction mixture containing 10-isopropoxy-benzo[b]quinoliziniumhexafluorophosphate (2 g; 5.2 mmol) and 1,1-diphenylethylene (1.129 g;6.2 mmol) in 50 mL of nitromethane was heated to reflux under nitrogenfor 16 hours. The reaction mixture was cooled, filtered, and thefiltrate was concentrated in vacuo to yield a foamy solid. The solidproduct was triturated with ether, filtered, and dried to yield 2.63 g(89.4%) of6,11-ethano-12,12-diphenyl-10-isopropoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷═10--OCH(CH₃)₂ ; X⁻ ═PF₆ ⁻).

(f)

6,11-Ethano-12,12-diphenyl-10-isopropoxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate(2.6 g: 4.6 mmol) was converted to the correspondingchloride by passing through Dowex® 1×2-200 (60 g) to afford 1.66 g(79.4%) of6,11-ethano-12.12-diphenyl-10-isopropoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷═10--OCH(CH₃)₂ ; X⁻ ═Cl⁻), m.p. 226°-30° C.

EXAMPLE 33 (a)

A mixture of 5 g (0.024 mol) of 3,5-difluorobenzyl bromide and 3.6 g(0.024 mol) of 2-(2'-pyridyl)-1,3-dioxolane was heated to stir at roomtemperature overnight and then filtered. The reaction mixture waspartitioned between water and ether, the aqueous phase was separated andtreated with a solution of potassium hexafluorophosphate in water. Thesolid residue was filtered and dried in vacuo to afford 9 g (76.9%) of1-(3,5-difluorobenzyl)-2-(2'-1,3-dioxolane)-pyridiniumhexafluorophosphate (Formula VI: R¹ ═R² ═H; R⁷ ═3,5-F₂ ; Z⁻ ═Br⁻).

(b)

A mixture of 1-(3,5-difluorobenzyl-2-(2'-1,3-dioxolane)pyridiniumhexafluorophosphate (9 g; 0.021 mol), polyphosphoric acid (90 g), and 9mL of methanesulfonic acid was heated at 110° C. for 7 hours and thenstirred at room temperature overnight. The reaction mixture was pouredinto 200 mL of water and a warm solution of 9 g of potassiumhexafluorophosphate in water was added with stirring. The resulting paleyellow solid product was filtered and dried to afford 6.5 g (86%) of8,10-difluoro-benzo[b]quinolizinium hexafluorophosphate (Formula II: R¹═R² ═H; R⁷ ═8,10-F₂ ; X⁻ ═PF₆ ⁻).

(c)

A reaction mixture containing 8,10-difluoro-benzo[b]quinoliziniumhexafluorophosphate (4 g; 11 mmol) and 1,1-diphenylethylene (4 mL; 22mmol) in 40 mL of nitromethane was heated to reflux under nitrogen for 3days. The reaction mixture was cooled, concentrated in vacuo, and theresidue was purified by chromatography on silica eluting withacetonitrile. The hexafluorophosphate was converted to the correspondingchloride by passing through Dowex® 1×2-200 to afford 1.68 g (35.5%) of6,11-ethanol-12,12-diphenyl-8,10-difluoro-6,11-dihydrobenzo[b]quinoliziniumchloride 1/4 hydrate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷═8,10-F₂ ; X⁻ ═Cl⁻).

EXAMPLE 34 (a)

A mixture of 9-methoxy-benzo[b]quinolizinium hexafluorophosphate (4 g)and 25 mL of 48% HBr was stirred and heated to 110° C. overnight. Theabove reaction mixture was filtered and the residue was washed withwater and dried to yield 1.8 g of 9-hydroxybenzo[b]quinolizinium bromide(Formula II: R¹ ═R² ═H; R⁷ ═9--OH; X⁻ ═Br⁻).

(b)

A reaction mixture containing 9-hydroxybenzo[b]quinolizinium bromide(1.35 g; 4.9 mmol) and 1,1-diphenylethylene (2.64 g; 14.7 mmol) in 20 mLof nitromethane was heated to reflux under nitrogen for 3 days. Thereaction mixture was cooled and the solid product was filtered,triturated with hexane (40 mL×3), and isolated by filtration. The solidproduct was dissolved in a mixture of 2N-HCl solution (150 mL), methanol(500 mL), and water (100 mL), filtered, and the solvent was removed invacuo to yield the residue. The residual product was washed with 20 mLof water and dried to afford 1.0 g (45.5%) of6,11-ethano-12,12-diphenyl-9-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═9--OH; X⁻═Cl⁻), as a gray solid, m.p. 270° C. (d).

EXAMPLE 35 (a)

To a suspension of methyltriphenylphosphonium bromide (7.14 g; 20 mmol)in ether was added at 0° C. n-butyllithium in hexane (8 mL; 20 mmol) andthe mixture was stirred at room temperature for 1 h. To the abovemixture was added 2.8 g (8.2 mmol) of 1,1-di(m-methoxyphenyl)ketone inether and the mixture was stirred for 10 minutes. The above reactionmixture was quenched with acetone (5 mL), stirred for 5 minutes,filtered, and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica eluting with hexane/ether (9:1) toafford 3.6 g (90%) of 1,1-di(3-methoxyphenyl)ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═3--CH₃ O-phenyl).

(b)

A reaction mixture containing benzo[b]quinolizinium perchlorate (2.5 g;8.9 mmol) and 1,1-di(3-methoxyphenyl)ethylene (3.0 g;12.5 mmol) in 100mL of nitromethane was heated to reflux under nitrogen for 48 h. Thereaction mixture was cooled, concentrated in vacuo, and the residue waspurified by chromatography on silica eluting with methylenechloride/ethyl acetate/methanol (7:2:1). The perchlorate was dissolvedin 200 mL of warm acetonitrile/methanol (2:1), treated with activatedcharcoal, filtered, and the filtrate was concentrated in vacuo to afford3.8 g (81.7%) of 6,11-ethanol12,12-di(m-methoxyphenyl)-6,11-dihydrobenzo[b]quinolizinium perchlorate(Formula I: R.sup.═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--CH₃ O-phenyl; X⁻ ═ClO₄⁻).

(c)

6,11-Ethano-12,12-di (m-methoxyphenyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (3.8 g) was converted to the corresponding chloride bypassing through Dowex® 1×2-200 to afford 2.8 g (84.8%) of6,11-ethano-12,12-di(m-methoxyphenyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--CH₃ O-phenyl; X⁻═Cl⁻), m.p. 164°-68° C.

EXAMPLE 36 (a)

To a suspension of methyltriphenylphosphonium bromide (3.25 g; 9.05mmol) in 100 mL of ether was added at 0° C. n-butyllithium in hexane(3.7 mL; 9.05 mmol) and the mixture was heated to stir at roomtemperature for 1 h. To the above mixture was added 2.8 g (8.2 mmol) of1,1-di(m-bromophenyl)ketone in 30 mL of tetrahydrofuran and the mixturewas stirred for 10 min. The above reaction mixture was quenched withacetone (5 mL), stirred for 5 minutes, filtered, and the filtrate wasconcentrated in vacuo. The residue in hexane/methylene chloride (3:1)was purified by chromatography on silica eluting with hexane to afford2.2 g (78.6%) of 1,1-di(m-bromophenyl)ethylene (Formula III: R³ ═R⁴ ═H;R⁵ ═R⁶ ═3--Br-phenyl).

(b)

A reaction mixture containing 1.51 g (5.4 mmol) of benzo[b]quinoliziniumperchlorate and 1,1-di(m-bromophenyl)ethylene (2.2 g; 6.5 mmol) in 70 mLof nitromethane was heated to reflux under nitrogen for 40 hours. Thereaction mixture was cooled, concentrated in vacuo, and the residue wastriturated with ether. The solid product was filtered and purified bychromatographic separations on silica (methylene chloride/ethylacetate/methanol (9:2:1)). The perchlorate was treated with warmacetonitrile/methanol and activated charcoal, filtered, and the filtratewas concentrated in vacuo to afford 2.7 g (81.8%) of6,11-ethano-12,12-di-(m-bromophenyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--Br-phenyl; X⁻═ClO₄ ⁻).

(c)

6,11 -Ethano-12,12-di(m-bromophenyl)-6,11 -dihydrobenzo[b]quinoliziniumperchlorate (2.7g; 4.5 mmol) was convened to the corresponding chlorideby passing through Dowex® 1×2-200 (50 g) to afford 2.16 g (86.4%) of6,11-ethano-12,12-di(m-bromophenyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--Br-phenyl; X⁻--Cl⁻), m.p. 194°-98° C.

EXAMPLE 37 (a)

To m-methoxyacetophenone (100 g, 0.665 mol) in 400 mL of methanol wasadded with cooling sodium borohydride (30.22 g, 0.799 mol) over a periodof 1 h and the mixture was stirred, poured into ice-water, andneutralized with conc. HCl. The above mixture was extracted with ether(3×400 mL), the organic layer was dried over sodium sulfate, andconcentrated. The residue was then distilled (149°-151° C. @ 25mm)(short path column) to afford 95.6 g (94%) ofm-methoxy-1-methyl-benzyl alcohol as a clear oil.

(b)

To a mixture of 71 g (0.467 mol) of m-methoxy-1-methyl-benzyl alcohol in800 mL of ether cooled to -20° C. was added in portions 100.4 mL (1.004mol) of n-butyllithium (10M) in hexane over a 40 min period, and thereaction mixture was heated to warm to room temperature and stirred for3 h. The above reaction mixture was cooled to -20° C., 59.98 g (0.56mol) of pyridine-2-carboxaldehyde was added to the mixture, and theresulting reaction mixture was heated to warm to room temperature andstirred for 2 h. Ammonium chloride solution and ethyl acetate were addedto the mixture. The aqueous layer was extracted with ethyl acetate, thecombined organic layer was dried over sodium sulfate, and concentratedto afford 63 g (53%) of2-[1-hydroxy-[6'-(1'-hydroxyethyl)-2'-methoxy]-benzyl]pyridine (FormulaX: R¹ ═H;R² ═CH_(3;) R⁷ ═2'-methoxy), as an oil which was recrystallizedfrom ethyl acetate/hexane as a tan solid.

(c)

A mixture of 5.4 g (0.021 mol) of2-[1-hydroxy-[6'-(1'-hydroxyethyl)-2'-methoxy]-benzyl]pyridine in POCl₃was refluxed for 1 h and then cooled. The reaction mixture was pouredinto ice with stirring, warmed, and 20 g of sodium perchlorate was addedwith stirring. The solid product precipitated was filtered, washed withwater, hexane, ethyl acetate, and ether, and then air dried to afford4.12 g (61.4%) of 10-methoxy-6-methylbenzo[b]quinolizinium perchlorate(Formula II: R¹ ═H; R² ═CH₃ ; R⁷ ═10--OCH₃ ; X⁻ ═ClO₄ ⁻), as a solid,m.p. 300°-302° C. (d) (recrystallization from methanol/acetonitrile).

(d)

A reaction mixture containing 10-methoxy-6-methylbenzo[b]quinoliziniumperchlorate (1.5 g; 4.63 mmol) and 1,1-diphenylethylene (1.1.7 g; 9.2mmol) in 50 mL of nitromethane was heated to reflux under nitrogen for72 hours. After adding additional 1,1-diphenylethylene (0.5 g), themixture was heated to reflux overnight. The reaction mixture was cooledand concentrated in vacuo to yield a foamy solid. The solid product wastreated with activated charcoal in boiling methanol/acetonitrile (3:1),filtered and the filtrate was concentrated in vacuo to afford 2.1 g(90.1%) of6,11-ethanol-12,12-diphenyl-10-methoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R³ ═R⁴ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═phenyl;R⁷═10--OCH₃ ; X⁻ --ClO₄ ⁻).

(e)

6,11-Ethano-12,12-diphenyl-10-methoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (2.1 g: 4.2 mmol) was converted to the correspondingchloride by passing through Dowex®1×2-200 (100 g) to afford 1.54 g(84.1%) of6,11-ethano-12,12-diphenyl-10-methoxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R³ ═R⁴ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═phenyl; R⁷═10--OCH₃ ; X⁻ --ClO₄ ⁻), m.p. 184°-188° C.

EXAMPLE 38 (a)

A mixture of 2.3 g of 10-methoxy-6-methylbenzo[b]quinoliziniumperchlorate in 35 mL of 48% HBr was heated at 100° C. for 14 h, cooledto room temperature, and was diluted with water. The resulting mixturewas heated to dissolve the solid product, filtered while hot, and thefiltrate was treated with 20 g of sodium perchlorate. The precipitatedsolid product was filtered, washed with ether, air dried to afford 2 g(90.9%) of 10-hydroxy-6-methyl-benzo[b]quinolizinium perchlorate(Formula II: R¹ ═H; R² ═CH₃ ; R⁷ ═10--OH; X⁻ --ClO₄ ⁻), m.p. 246°-248°C. (d).

(b)

A mixture of 1.5 g (5.5 mmol) of10-hydroxy-6-methyl-benzo[b]quinolizinium perchlorate and 1.98 g (10mmol) of 1,1-diphenylethylene in 75 mL of nitromethane was heated toreflux under nitrogen for 48 h. After adding additional1,1-diphenylethylene (0.5 g), the mixture was heated to reflux undernitrogen for an additional 48 h. The reaction mixture was cooled andconcentrated in vacuo to yield a yellow foam. The solid product wastreated with activated charcoal in boiling methanol/acetonitrile (3:1),filtered and the filtrate was concentrated in vacuo. The residue wascrystallized from isopropanol to afford 1.7 g (62.9%) of6,11-ethano-12,12-diphenyl-10-hydroxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R³ ═R⁴ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═phenyl; R⁷═10--OH; X⁻ --ClO₄ ⁻).

(c)

6,11-Ethano-12,12-diphenyl-10-hydroxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.7 g) was converted to the corresponding chloride salt bypassing the above salt through Dowex® 1×2-200 (100 g) to afford 1.05 g(75%) of6,11-ethano-12,12-diphenyl-10-hydroxy-6-methyl-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R³ ═R⁴ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═phenyl; R⁷═10--OH; X⁻ --Cl⁻) as a solid, m.p. 208°-212° C. (d).

EXAMPLE 39 (a)

To a suspension of methyltriphenylphosphonium bromide (6 g; 16.8 mmol)in 75 mL of ether was added at -20° C. n-butyllithium in hexane (6.8 mL;17 mmol) and the mixture was heated to stir at room temperature for 1 h.To the above mixture was added 2.5 g (15.4 mmol) of1,1-di(3-furyl)ketone in 50 mL of tetrahydrofuran in 10 minutes and themixture was stirred at room temperature for 2 h. To the above reactionmixture was added saturated ammonium chloride solution, and the mixturewas diluted with hexane. The organic layer was separated, washed withwater, dried, and concentrated in a5 vacuo. The residue was purified bychromatography on silica eluting with hexane to afford 1 g (40%) of1,1-di(3-furyl).ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl).

(b)

A reaction mixture containing benzo[b]quinolizinium perchlorate (1.4 g;4.95 mmol) and 1,1-di(3-furyl)ethylene (0.95 g; 5.9 mmol) in 50 mL ofnitromethane was heated to reflux under nitrogen for 3 h. The reactionmixture was cooled, concentrated in vacuo, and the residue was purifiedby chromatography on silica eluting with methylene chloride/ethylacetate/methanol (7:2:1) to yield a pale yellow solid. The solid productwas treated with warm methanol and activated charcoal, filtered, and thefiltrate was concentrated to give 1.9 g (86.3%) of6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻--ClO₄ ⁻), as a colorless solid.

(c)

6,11-Ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.9 g; 4.3 mmol) was convened to the corresponding chlorideby passing the salt through Dowex® 1×2-200 (50 g) to afford 1.3 g(80.2%) of6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻ --Cl⁻),m.p. 168°-71 ° C.

EXAMPLE 40 (a)+(b)

6,11 -Ethano-12,12-di(3-furanyl)-6,11 -dihydrobenzo[b]quinoliziniumperchlorate (3.5 g) dissolved in 50 mL of acetonitrile (hot) was passedthrough Dowex® 1×2-200 ion exchange resin (OH⁻), collecting 500 mL ofaqueous eluate. This eluate was extracted with 50 mL of ether, and theaqueous layer was treated with excess dibenzoyl-L(-)-tartaric acidmonohydrate. The aqueous layer was concentrated in vacuo, a pale-yellowresidue was triturated in 40 mL of ethanol with heating to afford 2.6 g(2 crops) of6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumo,o'-dibenzoyl-L(-)-tartarate (Example 40 (a)).

The above O,O'-dibenzoyl L(-)-tartrate salt was recrystallized from 20mL of hot ethanol, was converted to the corresponding chloride salt bypassing the salt through Dowex® 1×2-200 to afford 0.67 g of(+)-6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumchloride 3/2 hydrate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl;X⁻ --Cl⁻ ; Example 40(b)) as a white solid. [α]_(D) ²⁵ =+10.1°, in 10%DMSO_(d6) in CDCl₃, C=10 mg/mL.

EXAMPLE 41 (a)+(b)

The residue obtained on evaporation of all mother liquor from Example 40in methanol/acetonitrile (minimum) was made acidic by the addition of 2NHCl solution, diluted with 300 mL of water, and extracted with ether(3×75 mL). The aqueous layer was concentrated in vacuo, the residue wasdissolved in acetonitrile, and passed through Dowex® 1×2-200 ionexchange resin (OH⁻), then treated with 2.5 g of dibenzoyl-D(+)-tartaricacid monohydrate in acetonitrile. The solvent was concentrated to 1/3its volume and water was added to the mixture. The solid precipitate wasfiltered and recrystallized from ethanol to afford6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumdibenzoyl-D(+)-tartarate. (Example 41(a)).

The above D(+)-tartarate salt was converted to the correspondingchloride salt by passing the salt through Dowex® 1×2-200 to afford 0.67g of(-)-6,11-ethano-12,12-di(3-furanyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻ --Cl⁻ ;(-)-isomer), Example 41 (b)) as a white solid, [α]_(D) ²⁵,=+9.37° in DMFor [α]_(D) ²⁵ =-10.0° in 10% DMSO_(d6) in CDCl₃, C=10 mg/mL.

EXAMPLE 42 (a)

To a solution of 3-bromopyridine (9.84 g, 0.062 mol) in 300 mL of ethercooled to -78° C. was added n-butyllithium (1.6M, 41 mL, 0.066 mol) andstirred for 30 min. N-Methyl,N-methoxy-urethane (3.76 g, 0.028 mol) in20 mL of ether was added in 10 min, the mixture was stirred (-78° C.)for 1 h, allowed to warm to room temperature and stirred for 2 h. Thereaction mixture was quenched with 6N HCl (100 mL) and stirred. Theaqueous layer was basified with 10% NaOH solution, extracted with ethylacetate (2×) and methylene dichloride. The organic layer was dried oversodium sulfate, concentrated in vacuo, and the residue was purified bychromatography on silica (ethyl acetate, 10% methanol/ethyl acetate) toafford 1.7 g (33%) of di-(3-pyridyl)ketone.

(b)

To a suspension of methyl-triphenylphosphonium bromide (3.6 g; 10.1mmol) in 50 mL of ether was added at -20° C. 2.5M n-butyllithium inhexane (4 mL; 10.1 mmol) and the mixture was heated to stir at roomtemperature for 1 hour. To the above mixture was added 1.7 g (9.3 mmol)of 1,1-di(3-pyridyl)ketone in 50 mL of tetrahydrofuran and the mixturewas stirred at room temperature for 2 h. Ammonium chloride solution andethyl acetate (250 mL) were added to the above mixture, the organicphase was washed with water, brine, dried, and concentrated in vacuo.The residue was purified by chromatography on silica(ether/hexane/methanol, 5:4.5:0.5) to afford 0.9 g (52.9%) of1,1-di(3-pyridyl)-ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-pyridyl).

(c)

A reaction mixture containing benzo[b]quinolizinium perchlorate (1.15 g;4.12 mmol) and 1,1-di(3-pyridyl)ethylene (0.9 g; 4.94 mmol) innitromethane was heated to reflux under nitrogen for 120 h. The reactionmixture was cooled, concentrated in vacuo, the residue was treated with300 mL of warm methanol/acetonitrile (3:1) and activated charcoal, andthe mixture was filtered. The filtrate was concentrated in vacuo and theresidue was triturated with ether to yield 1.2 g (63.1%) of6,11-ethano-12,12-di(3-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-pyridyl; X⁻═ClO₄ ⁻).

(d)

6,11-Ethano-12,12-di(3-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.2 g; 2.6 mmol) was further purified by chromatography onsilica (1:2 ethanol/PAW), passed through Dowex® 1×2-200 resin (Cl⁻), andthen treated with 10% potassium hexafluorophosphate solution to yield1.1 g (83.3%) of6,11-ethano-12,12-di(3-pyridyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-pyridyl; X⁻ ═PF₆ ⁻).

(e)

The above hexafluorophosphate (1.05 g, 2.06 mmol) was convened to thecorresponding chloride by passing the salt through Dowex® 1×2-200 resin(Cl⁻) to afford 540 mg (65.8%) of6,11-ethano-12,12-di(3-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-pyridyl; X⁻ ═Cl⁻),m.p. 225° C. (d).

EXAMPLE 43 (a)

To a suspension of methyl-triphenylphosphonium bromide (31.36 g; 0.0878mol) in 500 mL of ether was added at -30° C. 10M n-butyllithium inhexane (8.78 mL; 0.078mol), the mixture was heated to warm and thenstirred at room temperature for 1 h. To the above mixture was added 21 g(0.0836 mol) of 1,1-di(p-chlorophenyl)ketone in 50 mL of tetrahydrofuranand the mixture was refluxed for 1 h, cooled, and filtered. The abovefiltrate was added to ammonium chloride solution, the resulting mixturewas extracted with ethyl acetate (3×150 mL), the organic layer was driedover sodium sulfate, and concentrated in vacuo to afford 22 g of crude1,1-di-(p-chlorophenyl)ethylene, (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═4--Cl-phenyl), as an off-white solid.

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(3 g; 9.8 mmol) and 1,1-di(p-chlorophenyl)ethylene (3.64g; 14.7 mmol) in60 mL of nitromethane was heated to reflux under nitrogen for 3 h. Thereaction mixture was cooled, filtered, and the filtrate was concentratedin vacuo. The dark residue was triturated with ether, filtered, anddried to give a pale brown solid product which was recrystallized frommethylene chloride/ethyl acetate to afford 3.8 g (62.3%) of6,11-ethano-12,12-di(p-chlorophenyl)-6,11-dihydrobenzo[b ]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═4--Cl-phenyl; X⁻ ═PF₆ ⁻), as a white solid, m.p. 212°-15° C.

EXAMPLE 44 (a)

To a suspension of methyltriphenylphosphonium bromide (30.96 g; 0.0825mol) in ether (500 mL) was added at -30° C. 10M n-butyllithium in hexane(8.66 mL; 0.0866 mol) and the mixture was heated to stir at roomtemperature for 1 h. To the above mixture was added 20 g (0.0825 mol) of1,1-di(p-methoxyphenyl)ketone in 50 mL of THF over a 4 min period andthe mixture was refluxed for 1 h and cooled. The above reaction mixturewas filtered and ammonium chloride solution was added to the filtrate.The above mixture was extracted with ethyl acetate (3×150 mL), theorganic layer was dried over sodium sulfate and concentrated in vacuo toafford 20.2 g of crude 1,1-di-(p-methoxyphenyl)ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═4--OCH₃ -phenyl).

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(3.52 g; 14.7 mmol) and 1,1-di(p-methoxyphenyl)-ethylene (3.52 g, 14.7mmol) in 60 mL of nitromethane was heated to reflux under nitrogen for18 h. The reaction mixture was cooled, filtered, and the filtrate wasconcentrated in vacuo. The resulting brown residue was triturated inether, the gray powder was dissolved in 10 mL of methylene chloride, 100mL of ethyl acetate, and hexane and the resulting solution wasconcentrated in vacuo to remove methylene chloride. Upon cooling thesolution, an off-white solid formed, was filtered and dried to afford 4g (66%) of6,11-ethano-12,12-di(p-methoxyphenyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4--OCH₃-phenyl; X⁻ ═PF₆ ⁻).

EXAMPLE 45 (a)

To a mixture of 5 g (0.024 mol) of p-trifluoromethylbenzoyl chloride in100 mL of THF was added in portions 3 g (0.027 mol) of LAH, stirred atroom temperature for 2 h, then refluxed for 2 h and cooled. To thereaction mixture was added 3 mL of water, 3 mL of 15% NaOH solution, and9 mL of water and the resulting mixture was refluxed for 10 min, cooled,and filtered. The filtrate was concentrated in vacuo to afford 5.5 g(100%) of p-trifluoromethyl-benzyl alcohol, as a clear oil.

(b)

A mixture of 5.5 g of p-trifluoromethyl-benzyl alcohol in 50 mL of 48%HBr was heated on a steam-bath for 6 h with stirring, and cooled. Water(100 mL) was added to the above mixture, and the aqueous layer wasextracted with ether, and the organic layer was concentrated in vacuo toafford 4.8 g of p-trifluoromethyl-benzyl bromide.

(c)

A mixture of 4.8 g (0.02 mol) of p-trifluoromethylbenzyl bromide and 3 g(0.019 mol) of 2-(2'-pyridyl)-1,3-dioxolane was heated to stir at roomtemperature 2 days, then filtered. The solid residue was washed withether and dried in vacuo to afford 6 g (76.9%) of1-(p-trifluoromethylbenzyl)-2-(1,3-dioxolon-2-yl)-pyridinium bromide(Formula VI: R¹ ═R² ═H; R⁷ ═4--CF₃ ; Z⁻ ═Br⁻)

(d)

A mixture of 1-(p-trifluoromethylbenzyl)-2-(1,3-dioxolan-2-yl)pyridiniumbromide (5 g; 12.8 mmol) in 50 g of polyphosphoric acid and 5 g ofmethanesulfonic acid was heated to 110° C. overnight. The reactionmixture was cooled, poured into water, and treated with 6 g of potassiumhexafluorophosphate in water. The solid product was filtered and driedto afford 3.05 g (60%) of 9-trifluoromethyl)-benzo[b]quinoliziniumhexafluorophosphate (Formula II: R¹ ═R² ═H; R⁷ ═9--CF₃ ; X⁻ ═PF₆ ⁻).

(e)

A reaction mixture containing 9-trifluoromethylbenzo[b]quinoliziniumhexafluorophosphate (2 g; 5 mmol) and 1,1-diphenylethylene (1.8 mL; 10mmol) in 30 mL of nitromethane was heated to reflux under nitrogen for 3days. The reaction mixture was cooled and filtered through a plug ofsilica gel (with 150 mL of acetonitrile), the filtrate was concentratedin vacuo, and the resulting residue dissolved in 10 mL of acetonitrilewas passed through Dowex® 1×2-200 (Cl⁻). The eluate was treated with 1 gof activated charcoal, filtered, and the filtrate was washed with 50 mLof ether, and the aqueous solution was concentrated in vacuo. The whitesolid residue was crystallized from water and dried in vacuo to afford3.04 g of6,11-ethano-12,12-diphenyl-9-trifluoromethyl-6,11-dihydrobenzo[b]quinoliziniumchloride 1/4 hydrate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷═9--CF₃ ; X⁻ ═Cl⁻), as a white solid, m.p. 180° C. (softens).

EXAMPLE 46 (a)

To a suspension of methyl triphenylphosphonium bromide (29.44 g; 0.0785mol) in 500 mL of ether was added at -30° C. 10M n-butyllithium inhexane (8.24 mL; 0.0824 mol) and the mixture was heated to warm and stirat room temperature for 1 h. To the above mixture was added 25 g (0.0785mol) of 3,3'-bis(trifluoromethyl)benzophenone in 50 mL oftetrahydrofuran and the mixture was refluxed for 1 h, cooled, filtered,and concentrated in vacuo. The above residue was chromatographed onsilica (hexane:CH₂ Cl₂ 2:1) to afford 22.3 g (89.9%) of1,1-di-(m-trifluoromethylphenyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═3--CF₃ -phenyl), as a yellow liquid.

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(4 g; 13 mmol) and 1,1-di(m-trifluoromethylphenyl)ethylene (4.95 g; 15.6mmol) in 55 mL of nitromethane was heated to reflux under nitrogen for24 h. The reaction mixture was cooled, filtered, and the filtrate wasconcentrated in vacuo. The solid product was triturated with ether,filtered, and dried to yield a tan powder. The product was purified bychromatography on silica eluting with methanol/methylene chloride (8:92)to afford 8.1g (90.3%) of6,11-ethano-12,12,-di(m-trifluoromethyl-phenyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3--CF3-phenyl; X⁻ ═PF₆ ⁻).

(c)

6,11-Ethano-12,12-di(m-trifluoromethylphenyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (8 g: 11.5 mmol) was converted to the correspondingchloride by passing the salt through Dowex® 1×2-200 (Cl⁻) (70 g) toafford 2.63 g (42.7%) of6,11-ethano-12,12-di(m-trifluoromethylphenyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--CF₃ -phenyl; X⁻═Cl⁻), as a tan powder, m.p. 155°-160° C.

EXAMPLE 47 (a)

To a mixture of 12.7 g (0.099 mol) of 2-thienylcarboxylic acid, 8.33 g(0.099 mol) of thiophene, and 34.9 mL of Amberlyst-15 in 250 mL ofnitromethane was added 34.9 mL (0.247 mol) of trifluoroacetic acid atroom temperature and stirred for 14 h. The reaction mixture wasfiltered, the filtrate was concentrated in vacuo, and a green oilresidue was chromatographed on silica (hexane/methylene chloride 1:1) toafford 8 g (41.6%) of di-(2-thienyl)ketone, as white needles.

(b)

To a suspension of methyl triphenylphosphonium bromide (15.46 g; 16.8mmol) in 250 mL of ether was added at -30° C. 10M n-butyllithium inhexane (4.3 mL; 43 mmol) and the mixture was heated to stir at roomtemperature for 1 h. To the above mixture was added 8 g (41 mmol) of1,1-di(2-thienyl)ketone in 30 mL of tetrahydrofuran over a 3 min period,the mixture was stirred at room temperature for 1 h and then filtered.To the above reaction mixture was added saturated ammonium chloridesolution, and the mixture was extracted with ethyl acetate (3×100 mL).The organic layer was separated, washed with water, dried, andconcentrated in vacuo to afford 1,1-di(2-thienyl)ethylene (Formula III:R³ ═R⁴ ═H; R⁵ ═R⁶ ═2-thienyl), as a brown oil.

(c)

A reaction mixture containing 6-methylbenzo[b]quinolizinium perchlorate(0.84 g; 2.86 mmol) and 1,1-di(2-thienyl)ethylene (0.768 g; 4 mmol) in50 mL of nitromethane was heated to reflux under nitrogen for 14 h. Thereaction mixture was cooled, filtered, and the solid product wastriturated with ether, filtered, and dried. The solid product wasrecrystallized from methylene chloride/ethyl acetate to yield6,11-ethano-12,12-di(2-thienyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═2-thienyl;X⁻ ═ClO₄ ⁻).

(d)

6,11-Ethano-12,12-di(thienyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate was converted to the corresponding chloride by passing thesalt through Dowex® 1×2-200 (Cl⁻) (55 g) to afford 0.595 g (49.4%) of6,11-ethano-12,12-di(2-thienyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═2-thienyl; X⁻═Cl⁻), as an off-whim solid, m.p. 173°-180° C.

EXAMPLE 48 (a)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(3.06 g; 10 mmol) and 1,1-di(2-thienyl)ethylene (2.2 g; 11.4 mmol) in 50mL of nitromethane was heated to reflux under nitrogen for 14 h. Thereaction mixture was cooled, filtered, and the brown solid product wastriturated with ether, filtered, and dried to yield a brown powder whichwas triturated with ethyl acetate/ether. The solid product was dissolvedin acetonitrile, treated with activated charcoal, filtered and thesolvent was concentrated to afford 2.3 g (40.5%) of6,11-ethano-12,12-di(2-thienyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═2-thienyl; X⁻ ═PF₆ ⁻).

(b)

6,11-Ethano-12,12-di(2-thienyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (2.3 g: 4 mmol) was convened to the correspondingchloride by passing the salt through Dowex® 1×2-200 (Cl⁻) (60 g) toafford 0.86 g (53%) of6,11-ethano-12,12-di(2-thienyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹⁻ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-thienyl; X⁻═Cl⁻), as an off-white solid, m.p. 162°-168° C.

EXAMPLE 49 (a)

To a suspension of 4-bromopyridine hydrochloride (21 g,0.1 mol) in 300mL of ether was added 200 mi., of saturated sodium bicarbonate and themixture was stirred for 5 min. The organic layer was dried over sodiumsulfate and concentrated in vacuo to afford 15.1 g (89.3%) of4-bromopyridine.

(b)

To a solution of n-butyllithium (2.5M, 39 mL, 0.096 mol) in 300 mL ofether cooled to -75° C. was added 4-bromopyridine (15.1 g, 0.095 mol) in100 mL of ether at such a rate to maintain the internal temperaturebelow -50° C. The resulting mixture was stirred at -75° C. for 15 min,and N-methyl,N-methoxyurethane (5.8 g, 0.043 mol) in 25 mL of ether wasadded over a 20 min period, and the mixture was warmed to roomtemperature and then stirred for 2 h. The mixture was quenched with 300mL of water and the layers were separated. The organic layer wasextracted with 6N HCl solution, and the aqueous layer was basified with10% NaOH solution. The basic solution was extracted with chloroform, theorganic layer dried over sodium sulfate, concentrated in vacuo, andpurified by chromatography on silica (ethyl acetate) to afford 3.9 g(48.7%) of di-(4-pyridyl)ketone.

(c)

A suspension of methyl triphenylphosphonium bromide (6.4 g; 18 mmol) in75 mL of ether was added at 0° C. to n-butyllithium in hexane (7.2 mL;18 mmol) and the mixture was heated to stir at room temperature undernitrogen for 1 h. To the above mixture was added 3 g (16 mmol) of1,1-di(4pyridyl)ketone in 20 mL of tetrahydrofuran over a 10 min periodand the mixture was stirred at room temperature for 30 minutes. Theabove reaction mixture was quenched with water and stirring. The organiclayer was separated, dried over sodium sulfate, and concentrated invacuo. The residue was purified by chromatography on silica eluting withethyl acetate/methylene chloride/methanol (7:2:1) to afford 2.2 g(73.3%) of 1,1-di(4-pyridyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═4-pyridyl).

(d)

A reaction mixture containing benzo[b]quinolizinium perchlorate (1.8 g;6.4 mmol) and 1,1-di(4-pyridyl)ethylene (2.1 g; 11.5 mmol) in 75 mL ofnitromethane was heated to reflux under nitrogen for 48 h. The reactionmixture was cooled, concentrated, the residue was treated with boilingwater and the mixture was filtered. The residual mixture was treatedwith charcoal and hot methanol, filtered, and the filtrate wasconcentrated in vacuo. The residue was further purified bychromatography on silica to afford 280 mg (9.4%) of6,11-ethano-12.,12-di(4-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4-pyridyl; X⁻═ClO₄ ⁻).

(e)

6,11 -Ethano-12,12-di(4-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (280 mg; 0.61 mmol) was converted to the correspondingchloride by passing the salt through Dowex® 1×2-200 resin to afford 220mg (9.4%) of6,11-ethano-12,12-di(4-pyridyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4-pyridyl; X⁻ ═Cl⁻).

EXAMPLE 50 (a)

A reaction mixture containing 6-methylbenzo[b]quinolizinium perchlorate(2.1 g; 7.1 mmol) and 1,1-di(3-furyl)ethylene (1.7 g; 10.1 mmol) in 50mL of nitromethane was heated to reflux under nitrogen for 16 h. Thereaction mixture was cooled, concentrated in vacuo, and the residue wastriturated with 100 mL of ethyl acetate/methanol (5:1). The solidproduct was filtered, washed with methanol, water, ether, and methanolto afford 1.5 g (46.8%) of6,11-ethanol-12,12-di(3-furanyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniumChloride (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H;R² ═CH₃ ; R⁵ ═R⁶ ═3-furanyl; X⁻═ClO₄ ⁻).

(b)

6,11-Ethano-12,12-di(3-furanyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.5 g; 3.3 mmol) was converted to the correspondingchloride by passing the salt through Dowex® 1×2-200 (Cl⁻) resin toafford 1.0 g (77.5%) of6,11ethano-12,12-di(3-furanyl)-6-methyl-6,11-dihydrobenzo[b]quinoliziniliumchloride (Formula I: R¹ ═R³ ═R¹¹ ═R⁷ ═H; R² ═CH₃ ; R⁵ ═R⁶ ═3-furanyl; X⁻═Cl⁻), m.p. 180°-84° C. (d).

EXAMPLE 51 (a)

To a suspension of NaH (4.7 g of 60% disp in oil) in DME (150 mL) wasadded cyclopropyl triphenylphosphonium bromide (44 g) and anhydrousethanol (10 drops). The resulting mixture was heated at 68° C. for 4 hand then 23 g of benzophenone was added in one portion and the reactionmixture was stirred under nitrogen at 70° C. for 5 h. The mixture wascooled to room temperature and stirred overnight under nitrogen. Water(300 mL) and 500 mL of hexane were added to the mixture, stirred for 10min, and the organic layer was dried over sodium sulfate andconcentrated in vacuo to afford 6.8 g (28.8% in 2 crops) ofdiphenylmethylenecyclopropane (Formula III: R³ and R⁴ together form acyclopropyl ring; R⁵ ═R⁶ ═phenyl) after chromatography on silica(hexane).

(b)

A reaction mixture of 6-methylbenzo[b]quinolizinium perchlorate (2.4 g;8.2 mmol) and diphenylmethylenecyclopropane (3.12 g; 15 mmol) innitromethane (75 mL) was heated to reflux under nitrogen for 48 h. Thereaction mixture was cooled, concentrated in vacuo, and the residue wastriturated with ether/ethyl acetate (5:1), and filtered. The solidproduct was purified by chromatography on silica eluting with methylenechloride/ethyl acetate/methanol (7:2:1) to yield a brown foamy solid.The product was treated with warm methanol/acetonitrile (5:1) andactivated charcoal and filtered. The filtrate was concentrated in vacuoto give 2.0 g (48.8%) of6,11-ethano-12,12-diphenyl-6-methyl-13,13-(spiropropane)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R⁷ ═H; R² ═CH₃ ; R³ and R⁴ together form acyclopropyl ring; R⁵ ═R⁶ ═phenyl; X⁻ ═ClO₄ ⁻).

(c)

6,11-Ethano-12,12-diphenyl-6-methyl-13,13-(spiropropane)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (2.0 g; 4 mmol) was converted to the corresponding chlorideby passing the salt through Dowex® 1×2-200 (Cl⁻) resin to afford6,11-ethano-12,12-diphenyl-6-methyl-13,13-(spirocyclopropane)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R⁷ ═H; R² ═CH₃ ; R³ and R⁴ together form acyclopropyl ring; R⁵ ═R⁶ ═phenyl; X⁻ ═Cl⁻), m.p. 184°-189° C.

EXAMPLE 52 (a)

A mixture of 2-pyridinecarboxaldehyde (300 g), 300 mL of ethyleneglycol, 3 L of toluene and 100 g of p-toluenesulfonic acid in a 5 L 3neck-flask equipped with a Dean-Stark head was refluxed for 4 h,separating the water formed. The mixture was concentrated in vacuo to1/2 of its volume, and poured into a 5 L flask containing a cold (5° C.)sodium bicarbonate solution. The aqueous layer was extracted withmethylene chloride (3×500 mL), the combined organic layer was dried oversodium sulfate, and concentrated in vacuo to yield a dark oil. The oilwas distilled (1 mm/100°-110° C.) to afford 349.1 g (82.4%) of2-(1,3-dioxoan-2-yl)pyridine.

(b)

A reaction mixture of 249.5 g (1.65 mol) of 2-(1,3-dioxolan-2-yl)pyridine and 339 g (1.98 mol) of benzyl bromide was heated briefly withstirring on a steam-bath to 50° C. After an exothermic reaction (125°C.), the mixture was heated at 100° C. on a steam-bath for 1 h to afford533 g (1.65 mol) of 1-benzyl-2-(1,3-dioxolan-2-yl)pyridinium bromide(Formula VI: R¹ ═R² ═R⁷ ═H; Z⁻ ═Br⁻).

(c)

To 1-benzyl-2-(1,3-dioxolan-2-yl)pyridinium bromide (1.65 mol) was added1 L of 48% HBr and 1 L of acetic acid with stirring and the mixture washeated on a steam-bath at 95° C. for 7 h. The mixture was concentratedin vacuo, the oil residue was combined with 2 L of isopropylacetate/isopropyl alcohol (1:1), and the solution was cooled. The yellowsolid was filtered, washed with ethyl acetate and dried to afford 292 g(68%) of benzo[b]quinolizinium bromide, (Formula II: R¹ ═R² ═R⁷ ═H; X⁻--Br⁻), as a light yellow solid.

(d)

To cooled (-78° C.) solution of 3-bromothiophene (16.3 g, 0.1 mol) inTHF (100 mL) was added under nitrogen, n-butyllithium (2.5M, 40 mL) andto the above mixture was added N-methyl-N-methoxyurethane (6.28 g, 0.047mol) in 5 mL of THF over a 0.5 h period and the mixture was allowed towarm to room temperature. The mixture was quenched with saturatedammonium chloride solution and the aqueous layer was extracted withether. The combined organic layer was dried over magnesium sulfate,concentrated in vacuo, and the oil residue was crystallized frommethanol to afford 1.465 g (16%) of 1,1-di-(3-thienyl)ketone, m.p.78°-80° C.

Alternatively, 1,1-di-(3-thienyl)ketone was prepared as follows:

To 100 mL of THF cooled to -78° C. under nitrogen was added 2.5Mn-butyllithium (36 mL), and 14.67 g (0.09 mol) of 3-bromothiophene wasadded and the resulting mixture was stirred for 30 min. To the abovemixture was added 3-thiophenecarboxaldehyde (10 g, 0.089 mol) in 10 mLof THF and the mixture was stirred, allowing it to reach roomtemperature. Saturated ammonium chloride solution was added to thereaction mixture, the aqueous layer was extracted with ether, and thecombined organic layer was concentrated in vacuo to yield 17.26 g(98.9%) of 1,1-di(3-thienyl)methanol, as an oil.

Chromium trioxide (1.4 g) was dissolved in 12 mL of water and 24 mL ofacetic acid, and the resulting mixture was added dropwise to1,1-di(3-thienyl)methanol in 30 mL of acetic acid over a 1 h period. Theabove mixture was stirred for 1 h with cooling (20° C.) in an ice-waterbath. The mixture was diluted with 150 mL of water, extracted withmethylene chloride, and the organic layer was washed with saturatedsodium bicarbonate solution, dried over sodium sulfate, and concentratedin vacuo to yield an oil, which was crystallized in methanol to afford1.85 g (47.7%) of 1,1-di(3-thienyl)ketone, as a solid, m.p. 79°-810 C.

(e)

To a suspension of methyl triphenylphosphonium bromide (15.7 g; 44 mmol)in 75 mL of ether was added under nitrogen at 0° C. 2.5M n-butyllithiumin hexane (17.6 mL; 43 mmol) dropwise (<5° C.) and the mixture wasallowed to warm and stir at room temperature for 1/2 h. To the abovemixture was added 7.85 g (44 mmol) of di(3-thienyl)ketone in 50 mL oftetrahydrofuran dropwise and the mixture was stirred at room temperaturefor 1/2 h. To the above reaction mixture was added 20 mL of acetone,concentrated in vacuo, and the residue was partitioned inwater/methylene chloride and methylene chloride was distilled in vacuo.The oil residue was distilled (0.02 mm/95°-100° C.) to afford 5.944 g(77.3%) of 1,1-di(3-thienyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═3-thienyl), as a colorless oil.

(f)

A reaction mixture containing benzo[b]quinolizinium perchlorate (0.839g; 3 mmol) and 1,1-di(3-thienyl)ethylene (0.68 g; 3.54 mmol) in 2 mL ofacetonitrile was allowed to reflux under nitrogen with stirring for 21h. The reaction mixture was concentrated in vacuo, the residue wasstirred in methylene chloride, and the white solid (975 mg) wasfiltered. The above solid was triturated in methanol (15 mL), dissolvedin water and passed through Dowex® 1×2×200 (Cl⁻) resin, the eluent wasconcentrated, and the residue was washed with acetonitrile and ether toafford 459 mg (58.6%) of 6,11-ethanol12,12-di(3-thienyl)-6,11-dihydrobenzo[b]quinolizinium chloride (FormulaI: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-thienyl; X⁻ ═Cl⁻).

EXAMPLE 53 (a)

To a suspension of 1,1-carbonyldiimidazole (90 g, 0.555 mol) in 400 mLof THF at 0° C. was added dropwise formic acid 25.5 g (0.555 mol) in 100mL of THF over a 15 min period. The mixture was warmed to roomtemperature and stirred for 1.5 h. The resulting solution was added viaa canula to the anion of methyl isocyanoacetate (generated by additionof the methyl isocyanoacetate in 75 mL of THF to a suspension ofpotassium t-butoxide at 0° C. and stirring for 15 min) at 0° C. Duringthe addition (exothermic), the reaction mixture reached to 20° C. andthe ice-bath was removed, stirring was continued at room temperature for1 h. The above mixture was quenched with 100 mL of acetic acid followedby 200 mL of water, THF was removed in vacuo, and 1000 mL of chloroformwas added to the residual mixture. The organic layer was washed withwater (2×200 mL), saturated sodium bicarbonate solution (1×100 mL),water, brine, and dried over sodium sulfate and concentrated in vacuo.The resulting residue was chromatographed on silica (methylenechloride/hexane/ether 7:2:1) to afford 23.5 g (37%) of methyl4.-oxazolecarboxylate.

(b)

To a suspension of methoxy-methylamine hydrochloride (2.3 g, 23.6 mmol)in 30 mL of dichloroethane at 0° C. was added dropwise 11.8 mL (23.6mmol) of trimethylaluminum. The mixture was stirred at 0° C. for 20 min,and methyl 4-oxazolecarboxylate (1 g, 7.9 mmol) in 20 mL ofdichloroethane was added in one portion. The mixture was poured into anice-cold solution of 0.5N HCl/methylene chloride (2:1) and stirred for10 min. The aqueous layer was extracted with methylene chloride (2×50mL), and the combined organic layer was washed with saturated ammoniumchloride solution, dried over sodium sulfate, and concentrated in vacuo.The resulting residue was purified by chromatography on silica(methylene chloride/ethyl acetate/methanol 6:3:1) to afford 1.0 g(81.9%) of 4-oxazolyl-N-methyl-N-methoxy-carboxamide.

(c)

To a solution of 4-oxazolyl-N-methyl-N-methoxy-carboxamide (2.76 g, 17.6mmol) in 250 mL of DME/THF (2:1) and 100 mL of DME cooled to -78° C.,was added a 1M solution of LAH (35.3 mL, 35.3 mmol) in THF over a 15 minperiod and the mixture was stirred at -78° C. for 1 h. After anadditional addition of 35 mL of LAH solution, the mixture was stirredfor 15 min, quenched with 2.6 mL of water, followed by 2 mL of 10% NaOHsolution and 2.6 mL of water. The above mixture was stirred at roomtemperature for 15 min, filtered, and the residue was washed with 600 mLof MDC/acetone (2:1). The combined filtrate was concentrated in vacuo,and the residue was purified by chromatography on silica (MDC/ethylacetate 6:1) to afford 0.62 g (36%) of 4-oxazolylcarboxaldehyde.

(d)

To a solution of oxazole (0.4 mL (6.2 mmol) in 20 mL of THE cooled to-78° C. under nitrogen was added 2.5M n-butyllithium (2.5 mL, 6.2 mmol).The mixture was stirred at -78° C. for 30 min and a solution of4oxazolylcarboxaldehyde (0.6 g, 6.2 mmol) in 25 mL of THF was addeddropwise. The resulting mixture was warmed to room temperature andstirred overnight. The reaction mixture was quenched with a suspensionof Dowex® 50×2-200 in methanol (20 mL) and stirred for 30 min, filtered,and the filtrate was concentrated in vacuo. The residue was dissolved inmethylene chloride, dried over magnesium sulfate, and concentrated invacuo. The resulting residue was purified by chromatography on silica(5% methanol in MDC) to afford 0.35 g (33.9%) of1,1-di(4-oxazolyl)methanol.

(e)

To a suspension of chromium trioxide (1.35 g, 13.5 mmol) in 75 mL ofmethylene chloride at 0° C. was added 2.1 g (12.6 mmol) of pyridine andthe mixture was allowed to warm to room temperature and stirred for 30min. To the mixture was added 1,1-di(4-oxazolyl)methanol (0.35 g, 2.1mmol) in 10 mL of MDC, and the mixture was stirred at room temperatureunder nitrogen for 15 min. The mixture was diluted with 100 mL of ethylacetate, stirred, filtered through a pad of florisil (4 inches) elutingwith 300 mL of ethyl acetate to afford 0.15 g (43.4%) of1,1-di(4-oxazolyl)ketone, as a white solid.

(f)

To a suspension of methyltriphenylphosphonium bromide (0.36 g; 1.01mmol) in 10 mL of THF was added under nitrogen at 0° C. 2.5Mn-butyllithium (0.4 mL, 1.01 mmol), and the mixture was stirred for 30min. To the above mixture was added di(4-oxazolyl)ketone (0.15 g, 0.92mmol) in 10 mL of THF and the mixture was stirred for 1 h. The mixturewas quenched with 25 mL of saturated ammonium chloride solution and 50mL of MDC was added and stirred. The organic layer was dried over sodiumsulfate, concentrated in vacuo, and the residue was purified bychromatography on silica (hexane/ethyl acetate 2:1) to afford 0.05 g(33.3%) of 1,1-di(4-oxazolyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═4-oxazolyl).

(g)

A reaction mixture containing benzo[b]quinolizinium perchlorate (71 mg;0.25 mmol) and 1,1-di(4-oxazolyl)ethylene (0.05 g; 0.3 mmol) in 10 mL ofnitromethane was heated at 100° C. for 2 h under nitrogen. The reactionmixture was concentrated in vacuo and the residue was dissolved in 5 mLof methanol and concentrated. The residue was triturated in 1 mL ofmethanol, the solid product was filtered, washed with 2 mL of coldmethanol and 10 mL of ether to afford 85 mg (75.8%) of6,11-ethano-12,12-di(4-oxazolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═4-oxazolyl; X⁻═ClO₄ ⁻), as a white solid, m.p. 236°-238° C.

EXAMPLE 54 (a)

To a solution of 4-picoline-N-oxide (20 g) in CH₂ Cl₂ (360 mL) was addedTMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride(16.6 mL) was added slowly dropwise. The mixture was stirred at RTovernight, poured onto 400 mL H₂ O, and 40 g NaCO₃. Separation of layersand evaporation of CH₂ Cl₂ gave 17.25 g of2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p.95°-98° C.

(b)

To a solution of 2-cyano-4-methylpyridine-N-oxide (3.29 g, 0.0279 mol)in 164 mL of methylene chloride at -78° C. was added 27.6 mL of DIBAL(H)and the mixture was stirred at -78 ° C. for 2 h. To the above mixturewas added 13 mL of HCl (conc.) and 52 mL of water, and the mixture waswarmed to room temperature. To the aqueous layer was added sodiumbicarbonate solution, the solution was extracted with ether, and thecombined organic layer was concentrated in vacuo. The residue waspurified by chromatography on silica (ether) to afford 0.5 g (14.8%) of4-methylpyridine-2-carboxaldehyde, as an oil.

(c)

A mixture of 1 g (8.26 mmol) of 4-methylpyridine-2-carboxaldehyde, and1.41 g (8.3 mmol) of benzyl bromide in 10 mL of sulfolane was stirredand heated on a steam-bath overnight. The resulting mixture wastriturated (repeatedly) with ethyl acetate and the solvent was decantedto isolate a dark gum. This residue was dissolved in water, and washedwith ether, and the aqueous solution was concentrated in vacuo to afford1-benzyl-4-methyl-2-formyl-pyridinium bromide, which was used withoutadditional purification.

(d)

A mixture of 1-(benzyl)-2-(formyl)-4-methylpyridinium bromide in 50 mLof 48% HBr was heated to 100° C. overnight. The reaction mixture wascooled and the solvent removed in vacuo. The residue was added to water(20 mL), and treated with 6 g of sodium perchlorate in water (100 mL).The solid product was filtered, dissolved in methylenechloride/methanol, and was purified by chromatography on silica elutingwith methylene chloride/methanol (1:1) to afford2-methyl-benzo[b]quinolizinium perchlorate, (Formula II: R¹ ═2--CH₃ ; R²═R⁷ ═H; X⁻ ═Br⁻) as a brown oil.

(e)

The above 2-methylbenzo[b]quinolizinium perchlorate and1,1-diphenylethylene (2 mL) in 50 mL of nitromethane was heated at 110°C. under nitrogen overnight. The reaction mixture was cooled,concentrated in vacuo, and the residue was purified by chromatography onsilica eluting with acetonitrile/methylene chloride (from 1:9 to 4:6) toafford 170 mg of6,11-ethano-12,12-diphenyl-2-methyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═2--CH₃ ; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═phenyl;X⁻ ═ClO₄ ⁻), as a brown oil.

EXAMPLE 55 (a)

To a suspension of methyl triphenylphosphonium bromide (15.6 g; 44 mmol)in 200 mL of ether cooled to -10° C. was added dropwise 2.2Mn-butyllithium in hexane (20 mL; 44 mmol) at -10° C. and the mixture wasallowed to warm to room temperature. To the above mixture cooled to -10°C. was added 10 g (44 mmol) of 1,1-di(m-chlorophenyl)ketone in oneportion, and the mixture was stirred overnight at room temperature. Themixture was quenched with water, extracted with ethyl acetate, and theorganic layer was washed with water, dried over sodium sulfate, andconcentrated in vacuo to afford 11.55 g of an oil. The oil was purifiedby chromatography on silica eluting with hexane to afford 6.5 g (65.3%)of 1,1-di(m-chlorophenyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═3--Cl-phenyl), as a colorless oil.

(b)

A reaction mixture containing 1.7 g (6.5 mmol) of benzo[b]quinoliziniumbromide and 1,1-di(m-chlorophenyl)ethylene (6.5 g; 26 mmol) in 25 mL ofacetonitrile/methanol (1:1) was allowed to reflux under nitrogen for 40hours. The reaction mixture was cooled, concentrated in vacuo, and theresidue was purified by chromatography on silica (ethyl acetate/ethanol1:1) to afford 2.15 g (65%) of a white solid. The white solid was addedto a mixture of 75 mL of water,75 mL of methanol, and Dowex® 1×2-200(Cl⁻), and the resulting mixture was heated with stirring and poured onDowex® 1×2-200 (Cl⁻) resin column to afford 1.2 g (36.3%) of6,11-ethano-12,12-di(m-chlorophenyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3--Cl-phenyl; X⁻═Cl⁻).

EXAMPLE 56

A reaction mixture containing 0.5 g (1.6 mmol) of benzo[b]quinoliziniumhexafluorophosphate, 0.001 g of p-toluenesulfonic acid, and1-phenyl-1-ethynyl-methanol (0.9 g; 6.4 mmol) in 10 mL of nitromethanewas heated to reflux under nitrogen for 4 h. The reaction mixture wascooled, concentrated in vacuo, and the residue (4.1:1 mixture ofisomers) was purified by chromatography on silica (methanol/methylenechloride 1:10) to afford 95 mg (13.6%) of6,11-ethano-12-phenyl-12-ethynyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═--C═CH; R⁶═phenyl; X⁻ ═PF₆ ⁻), single isomer, as a brown solid, m.p. 101°-106° C.

EXAMPLE 57 (a)

To a solution of 45.04 g (0.66 mol) of furan in 300 mL of ether wasadded 36.3 mL (0.363 mol) of 10M n-butyllithium at -20° C. and themixture was warmed to 0° C. and stirred for 1 h. The above mixture wascooled to -78° C. and N-methyl-N-methoxy-urethane (22 g, 0.165 mol) in20 mL of ether was added dropwise over a 20 min period and the resultingmixture was allowed to warm to room temperature for 1 h. The reactionmixture was quenched with 100 mL of ammonium chloride solution,extracted with ether (2×100mL), and the organic layer was dried oversodium sulfate and concentrated in vacuo to yield an oil. The above oilwas purified by chromatography on silica (methylene chloride) to afford26.5 g (95%) of 1,1-di(2-furyl)ketone, as a pale oil.

(b)

A suspension of methyl triphenylphosphonium bromide (11.56 g; 32.3 mmol)in 100 mL of ether was added at -30° C. 10M n-butyllithium in hexane(3.23 mL; 32.3 mmol) and the mixture was allowed to stir at roomtemperature for 1 h. To the above mixture was added 5 g (30.8 mmol) of1,1-di(2-furyl)ketone in 15 mL of tetrahydrofuran in 1 min and themixture was refluxed. The above mixture was cooled, filtered, andconcentrated to yield 4.92 g (100%) of 1,1-di(2-furyl)ethylene (FormulaIII: R³ ═R⁴ ═H; R⁵ ═R⁶ ═2-Furyl.

(c)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(5 g; 16.3 mmol) and 1,1-di(2-furyl)-ethylene (4.92 g; 30 mmol) in 100mL of nitromethane was allowed to reflux under nitrogen for 15 min. Thereaction mixture was cooled, triturated in ether for 20 min, and thesolvent was decanted to yield a brown powder. The above solid waspurified by two chromatographic purifications on silica(acetonitrile/methylene chloride, 1:9) to afford 1.2 g (15.1%) of6,11-ethano-12,12-di(2-furanyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-Furyl;X⁻ ═PF₆ ⁻), as a solid.

(d)

6,11-Ethano-12,12-di(2-furanyl)-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (1.2 g; 2.47 mmol) was converted to thecorresponding chloride by passing the salt through Dowex® 1×2-200 (Cl⁻)(60 g) to afford 0.91 g (98.9%) of6,11-ethano-12,12-di(2-furanyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-Furyl; X⁻ ═Cl⁻),m.p. 136°-141° C.

EXAMPLE 58 (a)

A suspension of methyl triphenylphosphonium bromide (31.22 g; 87.3 mmol)in 500 mL of ether was added at -30° C. 10M n-butyllithium in hexane(8.73 mL; 87.3 mmol) and the mixture was allowed to stir at roomtemperature for 1/2 h. To the above mixture was added 15 g (83.2 mmol)of 9-fluorenone in 50 mL of tetrahydrofuran and the mixture was refluxedfor 1 h. The above mixture was cooled to 0° C., filtered, andconcentrated to yield 11.3 g (76.3%) of 9-methylene-fluorene (FormulaIII: R³ ═R⁴ ═H; R⁵ ═R⁶ together form a 9-fluorene ring).

(b)

To a reaction mixture containing benzo[b]quinoliziniumhexafluorophosphate (6 g; 19.6 mmol) in 100 mL of nitromethane was added9-methylene-fluorene (6 g; 19.6 mmol) and the mixture was refluxed undernitrogen for 1 h. After the addition of another 2 g of9-methylene-fluorene, the reaction mixture was refluxed for 1 h. To therefluxing solution an additional 4 g of 9-methylene-fluorene was addedand refluxed for an additional 20 min, cooled, and filtered. Thefiltrate was concentrated, the residue was triturated in water, and thesolvent was decanted to yield a gray powder. The above powder waschromatographed on silica (11% acetonitrile in methylene chloride) toafford 2.3 g (21.3%) of6,11-ethano-12,12-spiro-9H-fluorenyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, as a yellow foam.

(c)

6,11-Ethano-12,12-spiro-9H-fluorenyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (2.3 g) was converted to the corresponding chlorideby passing the salt through Dowex® 1×2-200 (Cl⁻) (60g) to afford6,11-ethano-12,12-spiro-9H-fluorenyl-6,11 -dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; ##STR58## as a white solid,m.p. 236°-242° C. (d).

EXAMPLE 59 (a)

To a mixture of 10 mL (85.6 mmol) of 2-bromobenzaldehyde in 300 mL ofether cooled to -45° C. was added in portions 8.56 mL (85.6 mmol) of 10Mn-butyllithium in hexane over a 20 min period, and the reaction mixturewas stirred at -20 for 1/2 h. To the above reaction mixture cooled to-20° C., was added 8.98 mL (88.9 mmol) of 10M n-butyl-lithium in hexaneover a 10 min period, and the mixture was allowed to warm to roomtemperature and stirred for 1 h. The mixture was cooled to -20° C., and12.2 mL (128 mmol) of 2-pyridinecarboxaldehyde was added rapidly and themixture was allowed to warm to room temperature and stirred for 1 h. Theabove reaction mixture was poured into 150 mL of saturated ammoniumchloride solution with stirring, the aqueous layer was extracted withethyl acetate (3×200 mL), the combined organic layer was washed withbrine, dried over sodium sulfate, and concentrated in vacuo to yield abrown oil. The oil was purified by chromatography on silica eluting withmethylene chloride and then ether/hexane (9:1). The solvent wasconcentrated in vacuo, the brown oil was dissolved in methylenechloride/hexane, and removal of methylene chloride in vacuo to 1/2 ofits volume afforded 19.3 g (83.2%) of2-[1-hydroxy-6'-(1-hydroxypentyl)-benzyl]pyridine (Formula X: R¹ ═R⁷ ═H;R² ═n-butyl), as a yellow solid.

(b)

To a refluxing solution of 11.1 g (0.04 mol) of2-[1-hydroxy-6'-(1-hydroxypentyl)-benzyl]pyridine in 250 mL of benzenewas added 23.9 mL (0.14 mol) of triflic anhydride in 5 min, the mixturewas heated for 65 min and then cooled. The reaction mixture wasconcentrated in vacuo, the residual oil was triturated in ether anddecanted. The oil was chromatographed on silica (ethyl acetate/methylenechloride, 1:1 ) to afford an oil, which was treated with sodiumperchlorate solution. The salt was triturated in hot water, decanted,and the residue crystallized on cooling. The above solid wascrystallized (2×) from ethyl acetate/methylene chloride to afford 1.5 g(11%) of 6-butylbenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R⁷═H; R² ═n-butyl; X⁻ ═ClO₄ ⁻), as a pale solid, m.p. 174°-177° C.

(c)

A reaction mixture containing 6-butyl-benzo[b]quinolizinium perchlorate(0.75 g; 2.2 mmol) and 1,1-diphenylethylene (0.6 g; 3.3 mmol) in 50 mLof nitromethane was allowed to reflux under nitrogen for 16 h. Thereaction mixture was cooled, concentrated in vacuo and the resultingresidue was triturated in ether to yield a brown powder. The solidproduct was dissolved in methylene chloride, filtered, and the filtratewas chromatographed on silica (15% acetonitrile in methylene chloride)to afford 400 mg (35.3%) of 6,11-ethano-12,12-diphenyl-6-butyl-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H;R² ═n-butyl; R⁵ ═R⁶ ═phenyl; X⁻ ═ClO₄ ⁻), m.p. 134°-138° C.

EXAMPLE 60 (a)

A mixture of 2-pyridinecarboxaldehyde (267 g, 2.5 mol), ethylene glycol(310.35 g, 5 mol), and 118.8 g (0.62 mol) of p-toluenesulfonic acid in1.5 L of toluene placed in a 3 L flask fitted with a Dean Stark trap wasallowed to reflux until the removal of water was complete. The mixturewas concentrated in vacuo and the residue was poured into 800 mL ofice/10% potassium carbonate solution. The above mixture was extractedwith ether (2×500 mL), and the organic layer was dried over sodiumsulfate, filtered through an active charcoal/supercel and concentratedin vacuo to yield an oil. The oil was distilled (0.15 mm/90° C.) toafford 109.7 g (29.3%) of 2-(1,3-dioxolan-2-yl)-pyridine, as a paleyellow liquid.

(b)

To a solution of 75 g (0.3 mol) of 2,5-dibromotoluene in 1 L of carbontetrachloride was added 58.73 g (0.33 mol) of NBS and 50 mg of benzylperoxide, and the resulting mixture was refluxed with stirring for 24 h.The mixture was cooled, and concentrated in vacuo. The residue wascrystallized from hot methanol and washed with hexane to afford 54.5 g(55.7%) of 2.5-dibromobenzyl bromide as a solid.

(c)

A mixture of 25.03 g (0.165 mol) of 2-(1,3-dioxolan-2-yl)pyridine and2,5-dibromobenzyl bromide (54 g, 0.165 mol) in 60 mL of sulfolane washeated on a steam-bath for 6 h. The mixture was diluted with 600 mL ofethyl acetate, cooled, and the resulting solid product was isolated byfiltration. The above solid was triturated in 300 mL of ethyl acetate,the mixture was cooled, filtered and dried to afford 62.24 g (79%) of1-(2,5-dibromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide (FormulaVI: R¹ ═R² ═H; R⁷ ═2,5-Br₂ ; Z⁻ ═Br⁻), as a yellow solid, m.p. 135°-139°C.

(d)

A mixture of 400 g of 48% HBr and 52 g (0.125 mol) of1-(2,5-dibromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide was heatedat 100° C. with stirring for 39 h. The mixture was cooled to roomtemperature and poured into 400 g of ice, stirred, and filtered. Thefiltrate was diluted with 300 mL of water with stirring and filtered toyield a yellow solid. The solid was dissolved in hot water, filtered,and treated with sodium perchlorate solution to afford 21 g (39%) of7,10-dibromobenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═7,10-Br₂ ; X⁻ ═ClO₄ ⁻), as a yellow solid, m.p. >270° C.

(e)

A mixture of 2.5 g (6 mmol) of 7,10-dibromobenzo[b]quinoliziniumperchlorate and 1.15 g (7.2 mmol) of 1,1-di(3-furyl)ethylene in 50 mL ofnitromethane was refluxed for 20 min and cooled. The mixture wasconcentrated in vacuo, the residue (brown oil) was triturated in ether,and the resulting solid was crystallized from methanol to afford 3.49 g(99.7%) of6,11-ethano-12,12-di(3-furyl)-7,10-dibromo-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furyl; R⁷ ═7,10-Br₂; X⁻ ═ClO₄ ⁻) as an off white solid, m.p. 174°-179° C.

EXAMPLE 61 (a)

To a cooled (-78° C.) ether solution containing n-butyllithium (2.5M, 13mL, 32.5 mmol) was added 5.2 g (31 mmol) of 2-bromothiazole in 50 mL ofether over a 30 min period, and the mixture was stirred (-78° C.) for 1h. N-Methyl-N-methoxy-urethane (2.1 g, 15 mol) in 25 mL of ether wasadded to the above mixture over a 15 min period, the resulting reactionmixture was stirred at -78° C. for 1 h, warmed to room temperature, andstirred for 2 h. The above mixture was quenched with 3N HCl (200 mL) andstirred for 15 min. The aqueous layer was treated with solid sodiumbicarbonate (to pH 9), the precipitated solid was filtered, and washedwith water, and dried to yield a solid product. The solid product waspurified by chromatography on silica (hexane/ether/methylene dichloride4:2:1) to afford 1.7 g (54.8%) of 1,1-di(2-thiazolyl)ketone.

(b)

To a solution of 1,1-di(2-thiazolyl)ketone (1.96 g, 10 mmol) in 75 mL ofTHF cooled to 0° C. under nitrogen was added 15 mL (15 mmol) of 1Mtrimethylsilyl-methylmagnesium chloride over a 10 min period, and theresulting mixture was warmed to room temperature and stirred for 1 h.The reaction mixture was quenched with 3 mL of saturated ammoniumchloride solution, diluted with 100 mL of methylene chloride, andfiltered. The filtrate was washed with saturated ammonium chloridesolution, and the organic layer was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by passing through a padof silica, eluting with hexane/ether/methylene chloride 4:2:1) to afford1.1 g (38.5%) of 1,1-di(2-thiazolyl)-2-trimethylsilylethanol.

(c)

A mixture of 0.18 g (0.665 mmol) of benzo[b]quinolizinium perchlorate,0.24 g (0.85 mmol) of 1,1-di(2-thiazolyl)2-trimethylsilylethanol, and0.21 g (0.65 mmol) of p-toluenesulfonic acid in 10 mL of nitromethanewas refluxed under nitrogen for 3 h and cooled. The mixture wasconcentrated in vacuo, the residue was purified by chromatography onsilica (ethyl acetate, and then methylene chloride/ethylacetate/methanol 6:3:1) to yield a foamy solid which was triturated withisopropanol, filtered and dried in vacuo (65° C./60 h) to afford 30 mg(9.7%) of6,11-ethao-12,12-di(2-thiazolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═2-thiazolyl; X⁻═ClO₄ ⁻) as an off white solid, m.p. 235°-237° C.

EXAMPLE 62 (a)

To a cooled (-78° C.) ether (200 mL) solution containing n-butyllithium(2.5M, 13.5 mL, 33 mmol) was added 6.43 g (40.9 mmol) of2-trimethylsilyl-thiazole in 50 mL of ether over a 1 h period and themixture was stirred (-78° C.) for 1 h. N-Methyl-N-methoxy-urethane (2.32g, 17.5 mol) in 50 mL of ether was added to the above mixture over a 15min period, the resulting reaction mixture was stirred at -78° C. for 1h, and then warmed to room temperature with stirring. The above mixturewas quenched with 3N HCl and stirred for 2 h. The aqueous layer wastreated with solid sodium bicarbonate (to pH 8), diluted with saturatedammonium chloride solution, and extracted with chloroform (3×150 mL).The combined organic layer (including the original ether layer) wasdried over sodium sulfate, and concentrated in vacuo. The residue wastriturated with ether (50 mL), filtered, and dried to afford 160 mg(4.6%) of 1,1-di(5-thiazolyl)ketone.

(b)

To a suspension of methyl triphenylphosphonium bromide (0.35 g; 1 mmol)in 15 mL of THF was added under nitrogen at 0° C. 2.5M n-butyllithium(0.4 mL, 1 mmol) and the mixture was stirred for 1 h. To the abovemixture was added 1,1-di(5-thiazolyl)ketone (0.16 g, 0.82 mmol) in 5 mLof THF and the mixture was stirred under nitrogen at room temperaturefor 2 h. The mixture was quenched with 2 mL of acetone, diluted with 50mL of ether, and filtered. The filtrate was concentrated in vacuo andthe residue was purified by chromatography on silica (ether) to afford0.035 g (21.8%) of 1,1-di(5-thiazolyl)ethylene (Formula III: R³ ═R⁴═H;R⁵ ═R⁶ ═5-thiazolyl).

(c)

A reaction mixture containing benzo[b]quinolizinium perchlorate (450 mg;0.165 mmol) and 1,1-di(5-thiazolyl)ethylene (0.035 g; 0.18 mmol) in 8 mLof nitromethane was heated at 90° C. for 16 h under nitrogen. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin 25 mL of boiling methanol with charcoal, filtered, and concentratedin vacuo. The residue was triturated with 10 mL of methanol/isopropanol(1:2), and the solid product was filtered and dried to afford 22 mg(28.2%) of6,11-ethano-12,12-di(5-thiazolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-thiazolyl; X⁻═ClO₄ ⁻), as a solid.

EXAMPLE 63 (a)

To a cooled (-78° C.) 200 mL of THF solution containing 19.8 g (0.1 mol)of 1-(trimethylsilylethoxymethyl)pyrazole was added n-butyllithium(2.5M, 40 mL, 0.1 mol) over a 30 min period, and the mixture was stirredat -78° C. for 2 h. To the above mixture was added at -78° C.N-methyl-N-methoxyurethane (6.7 g, 0.05 mol) in 30 mL of THF and themixture was stirred for 1 h, and then was allowed to warm to roomtemperature and stirred for 14 h under nitrogen. The above mixture wasquenched with 100 mL of saturated ammonium chloride solution and stirredfor 10 min. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was purified by chromatography onsilica (hexane/ether 4:1) to afford 15 g (71.4%) of 1,1-di[5-(1-trimethylsilyl-ethoxymethyl)pyrazolyl]ketone.

(b)

To a suspension of methyl triphenylphosphonium bromide (7.3 g; 0.02 mol,dried in vacuo) in 150 mL of ether was added under nitrogen at 0° C.2.5M n-butyllithium (8 mL, 0.02 mol) and the mixture was stirred for 1h. To the above mixture was added1,1-di[5-(1-trimethylsilylethoxymethyl)pyrazolyl]ketone (7.2 g, 0.017mol) in 30 mL of ether over a 10 min period, then the mixture wasstirred for 10 min at room temperature, refluxed for 15 min, and themixture was cooled. The above mixture was quenched with 2 mL of acetone,stirred for 10 min, filtered through a pad of supercel, and washed withether. The filtrate was concentrated in vacuo and the residue waspurified by chromatography on silica (hexane/methylene chloride/ether6:3:1) to afford 3.6 g (50.7%) of1,1-di[5-(1-trimethylsilylethoxymethyl)pyrazolyl]ethylene (Formula III:R³ ═R⁴ ═H; R⁵ ═R⁶ ═5-[1-(CH₃)₃ Si(CH₂)₂ OCH₂)pyrazolyl]).

(c)

A reaction mixture containing benzo[b]quinolizinium perchlorate (1.9 g;6.8 mmol) and 1,1-di[5-(1-trimethylsilylethoxymethyl)pyrazolyl]ethylene(3.6 g; 8.6 mmol) in 70 mL of nitromethane was heated at 105° C. for 9 hunder nitrogen. The reaction mixture was concentrated in vacuo, theresidue was triturated with 50 mL of isopropanol, filtered, and dried toafford 4 g (84.2%) of6,11-ethano-12,12-di[5-(1-trimethylsilyl-ethoxymethyl)pyrazolyl]6,11-dihydrobenzo[b]quinoliziniumperchlorate, (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-[1-(CH₃)₃Si(CH₂)₂ OCH₂)pyrazolyl]; X⁻ ═ClO₄₋), as a solid, m.p.123°-125° C.

(d)

To a solution of 525 mg (0.74 mmol) of6,11-ethano-12,12-1,1-di[5-(1-trimethyl-silylethoxymethyl)pyrazolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 15 mL of dichloroethane was added 5 mL of trifluoroaceticacid and the mixture was stirred at room temperature for 2 h. Thereaction mixture was concentrated in vacuo to afford6,11-ethano-12,12-di(5-pyrazolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-pyrazolyl; X⁻═ClO₄ ⁻), as a white solid, which was dissolved in 75 mL ofethanol/isopropanol (2:1), heated with charcoal, filtered, andconcentrated. The resulting residue was dissolved in 25 mL of water,filtered, and the filtrate was concentrated in vacuo to yield a whitesolid. The above white solid was purified by chromatography on silica(E/PAW) and the residue was dissolved in water, filtered, and thefiltrate was concentrated in vacuo to afford the purified perchloratesalt, m.p. 178°-180° C.

EXAMPLE 64 (a)

To a cooled (-78° C.) solution of 46.3 g (0.3 mol) of1-(1-pyrrolidinomethyl)pyrazole in anhydrous THF (1 L) was addedn-butyllithium (2.5M, 123 mL, 0.3 mol), and the mixture was stirred at-78° C. for 1.5 h. To the above mixture was added DMPU and stirred at-78° C. for 20 min, and then N-methyl-N-methoxy-urethane (79 g, 0.612mol) in 150 mL of THF, and the mixture was allowed to warm to roomtemperature and stirred overnight. The above mixture was quenched with200 mL of water and stirred. The aqueous layer was extracted with ethylacetate (2×100 mL), and the organic layer was dried over sodium sulfate,and concentrated in vacuo. The residue was dissolved in 500 mL ofdioxane/ether (2:1), diluted with 300 mL of 6N HCl and stirred undernitrogen for 20 h.

The layers were separated, the organic layer was washed with brine, andthe aqueous layer was extracted with THF/ether (5×400 mL). The combinedorganic layer was dried over sodium sulfate and concentrated to afford45 g of a mixture that contained 25% (by NMR) of1,1-di-(5-pyrazolyl)-ketone.

(b)

To a suspension of 3.7 g (0.15 mol) of NaH in DMF at 0° C. was added11.25 g (0.07 mol) of 1,1-di-(5-pyrazolyl)-ketone, and the mixture wasallowed to warm to room temperature and stirred for 1 h. To the abovemixture was added p-methoxybenzyl chloride (24 g, 0.15 mol) in 25 mL ofDMF and the mixture was stirred at room temperature under nitrogen for20 h. The mixture was concentrated in vacuo, and the residue waspurified by chromatography on silica (hexane/ethanol) to afford 6.2 g(22%) of1-[1-p-methoxybenzyl)-pyrazol-3-yl]-1-[(1-p-methoxybenzyl)-pyrazol-5-yl)-ketone and 18 g (63.9%) of1,1-di,[(1-p-methoxybenzyl)-pyrazol-3-yl]-ketone.

(c)

To a suspension of potassium t-butoxide (7 g, 0.062 mol) in 650 mL ofTHF at 0° C. was added methyl triphenylphosphonium bromide (22.3 g;0.062 mol) under nitrogen and the mixture was stirred at roomtemperature for 1.5 h. To the above mixture was added1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)-ketone in 200 mL of THF andthe mixture was stirred at room temperature under nitrogen for 30 min.The above mixture was quenched with 15 mL of saturated ammonium chloridesolution, and 700 mL of ether was added with stirring. The organic layerwas dried over sodium sulfate, concentrated in vacuo, and the residuewas purified by chromatography on silica (ether/hexane 1:1) to afford14.9 g (89.7%) of 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene(Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═1-p-methoxybenzyl-3-pyrazolyl).

(d)

A reaction mixture containing benzo[b]quinolizinium perchlorate (9.5 g;6.8 mmol)and 1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)ethylene (14.9 g;0.034 mol) in 300 mL of nitromethane was refluxed for 16 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas triturated with 400 mL of methanol, and the solid was filtered, anddried (60° C.) to afford 22.1 g (85.6%) of6,11-ethano-12,12-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)]-6,11-dihydrobenzo[b]quinolizinium perchlorate (FormulaI: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═1-p-methoxybenzyl-3-pyrazolyl; X⁻═ClO₄ ⁻), as a solid.

(e)

A solution of 5.6 g (8.2 mmol) of6,11-ethano-12,12-1,1-di-[(1-p-methoxybenzyl)-pyrazol-3-yl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 200 mL of trifluoroacetic acid was refluxed undernitrogen for 36 h and then stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo, the residue was trituratedwith ethyl acetate, and the solid product was filtered. The resultingsolid dissolved in hot methanol/acetonitrile (3:1) was treated withactivated charcoal, filtered, and the filtrate was concentrated in vacuoto afford 2.6 g (72.2%) of 6,11-ethanol12,12-di-[(pyrazol-5-yl)-6,11-dihydrobenzo[b]quinolizinium perchlorate(Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-pyrazolyl; X⁻ ═ClO₄ ⁻), asa solid.

The above product was further purified by chromatography on silica(ethyl acetate/PAW, 2:1 and then ethyl acetate/PAW, 1:1) and theresulting solid was triturated with acetonitrile, the solid was filteredand recrystallized from ethyl acetate to yield 2.5 g of6,11-ethano-12,12-di-[(pyrazol-5-yl)-6,11-dihydrobenzo[b]quinoliziniumacetate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-pyrazolyl; X⁻═--OAC).

(f)

6,11-Ethano-12,12-di-[(pyrazol-5-yl)-6,11-dihydrobenzo[b]quinoliziniumacetate was convened to the corresponding chloride salt by passing theacetate salt through Dowex® 1×2-200 (Cl⁻) (200 g) to afford 1.9 g(80.8%) of 11-ethano-12,12-di-[(pyrazol-5-yl)-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H;R⁵ ═R⁶═5-pyrazolyl; X⁻ ═Cl⁻), as a solid.

EXAMPLE 65 (a)

To 300 mL of THF was added with cooling (ice-bath) 300 mL (0.3 mol) of1M TiCl₄ in methylene chloride and the mixture was stirred for 10 min.To the above mixture was added at room temperature 90.5 mL (0.6 mol) ofTMEDA, the mixture was stirred for 10 min, and then 44.12 g (0.675 mol)of Zn dust was added with cooling to maintain the mixture at roomtemperature and stirred for 40 min. To the resulting reaction mixturewas added dropwise to a mixture of ethyl 3-furoate (10.5 g, 0.075 mol),31 g (0.165 mol) of dibromoethane in 200 mL of THF, and the mixture wasstirred at room temperature for 2.5 h. After adding 90 mL of aqueouspotassium carbonate solution, the mixture was concentrated in vacuo, theresidue was diluted with 20 g of basic alumina, passed through a basicalumina column (ether/TEA 200:1), and the eluent was concentrated. Theresidue was triturated in ether (200 mL), filtered, and the filtrate wasdistilled (80°-95° C./25 mm) to afford 6.2 g (54.3%) of1-(3-furyl)-1-ethoxy-2-methylethylene (Formula III: R³ ═CH₃ ; R⁴ ═H; R⁶═CH₃ CH₂ O; R⁵ ═3-Furyl; and Formula III: R³ ═H; R⁴ ═CH₃ ; R⁶ ═3-Furyl;R⁵ ═CH₃ H₂ O).

(b)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(10.98 g; 35 mmol) and 1-(3-furyl)-1-ethoxy-2-methylethylene (6 g; 0.039mol) in 100 mL of nitromethane was heated at 60°-100° C. for 2 h,cooled, and filtered. The reaction mixture was concentrated in vacuo,the residue was triturated in ether and decanted. The brown solid wasdried, ground to powder, and treated with activated charcoal in hotethyl acetate. The above mixture was filtered through celite, andconcentrated to afford 6,11-ethano-12-(3-furyl)-12-ethoxy-13-methyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, as a brown solid [2.1:1:4.04 mixture geometries].

(c)

The mixture of Example 65(b) was subjected to fractional trituration(5×) in hot isopropanol to yield hot isopropanol insoluble6,11-ethano-12-(3-furyl)-12-ethoxy-13-methyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate, (Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; R³ ═CH₃ ; R⁵═3-Furyl; R⁶ ═CH₃ CH₂ O; X⁻ ═PF₆ ⁻) as a single geometric isomer, m.p.195°-197° C.

EXAMPLE 66 (a)

To a solution of furan-3-carboxylic acid (36 g, 0.32 mol) in 250 mL oftoluene was added 49 mL (0.385 mol) of oxalyl chloride and 1 drop ofpyridine and the mixture was heated at 80°-90° C. for 1.5 h. The mixturewas cooled to room temperature, N,O-dimethylhydroxylamine hydrochloride(35 g, 0.36 mol), 4-dimethylaminopyridine (DMAP, 1.8 g, 0.0147 mol), and600 mL of methylene chloride were added. The mixture was cooled to 0°C., 68.4 g of pyridine was added slowly, the mixture was allowed to warmto room temperature and stirred for 2 h. The mixture was filtered, andthe filtrate was washed with water, 5% aqueous dimethylaminopropylamine,water, 6N HCl solution, water, and brine. The organic layer was driedand concentrated in vacuo, and the residue was distilled (b.p. 85°-87°C./0.2 mm) to afford 44 g (88.7%) of3-(N-methyl-N-methoxycarbamoyl)furan.

(b)

To a solution of n-butyllithium (2.5M, 28 mL, 0.07 mol) in 150 mL ofether at -78 ° C. was added a solution of 3-bromofuran (10 g, 0.0628mol) in 30 mL of ether over a 20 min period and the mixture was stirredat -78° C. for 20 min. To the above mixture was added3-(N-methyl-N-methoxycarbamoyl)furan (9.16 g, 0.059 mol) in 30 mL ofether over a 15 min period and the mixture was stirred at roomtemperature for 1/2 h. The reaction mixture was quenched with 200 mL ofammonium chloride solution, 500 mL of methylene chloride was added andthe mixture was stirred. The organic layer was dried over sodiumsulfate, concentrated in vacuo, and the residue was triturated with 100mL of hexane/TBME (9:1). The solid product was filtered and washed withTBME to afford 7.5 g (78.3%) of di-(3-furyl)ketone.

(c)

A suspension of methyl triphenylphosphonium bromide (145 g; 0.405 mol,dried at 60° C.) in 1 L of ether was added at -20° C. n-butyllithium inhexane (2.5M, 162 mL; 0.405 mol) and the mixture was allowed to stir atroom temperature for 1 h. To the above mixture was added 60 g (0.37 mol)of 1,1-di(3-furyl)ketone in 450 mL of DME/THF/DMPU (2:2:0.5) in 10minutes and the mixture was stirred at room temperature for 1 h. To theabove reaction mixture was added saturated ammonium chloride solution(250 mL), and the mixture was diluted with 500 mL of water. The organiclayer was separated, washed with water (2×500 mL), dried, andconcentrated in vacuo. The residue was purified by chromatography onsilica (hexane, then 10% ether/hexane) to afford 51 g (86%) of1,1-di(3-furyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furanyl).This product was further distilled (b.p. 60°-63° C./0.01 mm).

(d)

To a mixture of 14 g (0.1 mol) of m-methoxybenzyl alcohol in 300 mL ofether cooled to -40° C. was added 12.8 mL (0.2 mol) of 2.5Mn-butyllithium over a 30 min period and the reaction mixture was slowly(removing a bath) warmed to room temperature and stirred for 30 minutes.To the above mixture 11.77 g (0.1 mol) of TMEDA was added. The abovereaction mixture was cooled to -20° C., 16.05 g (0.15 mol) of2-pyridinecarboxaldehyde was added to the mixture, and the resultingreaction mixture was allowed to warm to room temperature with stirring.After 1 hour, ammonium chloride solution was added to the mixture. Thediol was extracted with ethyl acetate, dried over sodium sulfate, andthe solvent was removed in vacuo. The residue was triturated in ether,filtered and the solid was washed with ether to afford 14.6 g (58%) of2-[1-hydroxy-(2'-methoxy-6'-hydroxymethyl)-benzyl]pyridine (Formula X:R¹ ═R² ═H; R⁷ ═2'--OCH₃).

(e)

To a stirred POCl₃ (75 mL) was added slowly 14.6 g (0.059 mol) of2-[1-hydroxy-(2'-methoxy-6'-hydroxymethyl)benzyl]-pyridine and thereaction mixture was heated on a steam-bath for 2 h and cooled. Theabove mixture was poured into ice-water and stirred for 1/2 h. Sodiumperchlorate (excess) was added to the above mixture, the solidprecipitate was filtered and washed with water. The solid product wasrecrystallized from acetonitrile to afford 4 g of10-methoxy-benzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═10--OCH₃ ; X⁻ ═ClO₄ ⁻).

(f)

A mixture of 3.1 g (0.01 mol)) of 10-methoxybenzo[b]quinoliziniumperchlorate and 2.4 g (0.01 mol) of 1,1-di-(3-furyl)ethylene in 75 mL ofacetonitrile was allowed to reflux for 18 h. The mixture was cooled,filtered, and the filtrate was concentrated in vacuo. The residue wastriturated in ether, and filtered to yield 4.6 g of a crude product.This solid was purified by chromatography on silica (methylenechloride/ethyl acetate/methanol, 7:2:1) to afford 4.1 g (87.4%) of6,11-ethano-12,12-di-(3-furyl)-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate. (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furyl; R⁷═10--OCH₃ ; X⁻ ═ClO₄ ⁻) as a solid.

(g)

6,11-Ethano-12,12-di-(3-furyl)-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (4.1 g; 8.73 mmol) was converted to the correspondingchloride by passing the salt through Dowex® 1×2-200 (Cl⁻) to afford 3.4g (96%) of6,11-ethano-12,12-di(3-furanyl)-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furyl; R⁷ ═10--OCH₃ ;X⁻ ═Cl⁻).

EXAMPLE 67 (a)

To a cooled (-78° C.) 1 L ether solution containing 25 g (0.105 mol) of2,6-dibromopyridine was added n-butyllithium (2.5M, 42 mL, 0.105 mol)over a 20 min period, and the mixture was stirred at -78° C. for 1/2 h.To the above mixture was added at -78° C. N-methyl-N-methoxy-urethane(6.6 g, 0.049 mol) in 50 mL of ether and the mixture was stirred at -78° C. for 1 h, and was allowed to warm to room temperature and stirredfor 3 h. The above mixture was quenched with 100 mL of saturatedammonium chloride solution and stirred overnight. The organic layer wasdried over sodium sulfate, concentrated in vacuo, and the residue wastriturated with ether, filtered, and the solid residue was dried toafford 11 g (65.47%) of 1,1-di[(6-bromo)-2-pyridyl]ketone. This solidproduct was recrystallized from ethyl acetate to yield 8.2 g of theketone.

(b)

To 200 mL of methanol was added in portions 2.3 g (0.1 mol) of sodiumand the mixture was stirred under nitrogen for 2 h.1,1-di[(6-bromo)-2-pyridyl]ketone (8 g, 0.024 mol) was added to theabove mixture, and the reaction mixture was refluxed under nitrogen for24 h. An additional 2 g of sodium methoxide was added to the mixture andrefluxed for 48 h, and cooled. The mixture was diluted with ether,washed with saturated ammonium chloride solution, and the organic layerwas dried over sodium sulfate, and concentrated in vacuo. The residuewas purified by chromatography on silica (ether/hexane, 2:8) to afford2.5 g (42.7%) of 1,1-di(6-methoxypyridin-2-yl)methanol. In addition, 100mg of 1,1-di(6-methoxypyridin-2-yl)ketone was also isolated from thechromatographic fractions.

(c)

To a solution of 10.2 8 (0.13 mol) of pyridine in 500 mL of methylenechloride at 0° C. was added CrO₃ (6.5 8, 0.011 mol) in portions, and themixture was stirred at 0° C. for 1 h. To the above mixture was added1,1-di(6-methoxypyridin-2-yl)methanol (2.5 g, 0.011 mol) in 50 mL ofmethylene chloride and the mixture was stirred for 2 h at roomtemperature. The reaction mixture was diluted with ethyl acetate,filtered through celite, and the filtrate was concentrated in vacuo toafford 1.65 8 (66%) of 1,1-di(6-methoxypyridin-2-yl)ketone.

(d)

To a suspension of 1.25 8 (0.011 mol) of potassium t-butoxide in 30 mLof THF at 0° C. was added methyl triphenylphosphonium bromide (3.57 g;0.01 mol) and the mixture was stirred at room temperature for 1 h. Tothe above mixture was added 1,1-di(6-methoxypyridin-2-yl)ketone (1.6 g,0.0657 mol) in 30 mL of THF and the mixture was stirred for 30 min atroom temperature under nitrogen. The above mixture was quenched withsaturated ammonium chloride solution, diluted with ether, filtered, theaqueous layer was extracted with ether, and the combined organic layerwas filtered. The above filtrate was concentrated in vacuo, and theresidue was chromatographed on silica (hexane/ether, 8:2) to afford 0.94g (59.4%) of 1,1-di(6-methoxypyridin-2-yl)ethylene (Formula III: R³ ═R⁴═H;R⁵ ═R⁶ ═6-OCH₃₋₂ -Pyridyl).

(e)

A mixture of 1 g (3.5 mmol) of benzo[b]quinolizinium perchlorate and0.94 g (3.8 mmol) of 1,1-di(6-methoxypyridin-2-yl)ethylene in 30 mL ofnitromethane was allowed to reflux under nitrogen for 16 h. The mixturewas cooled, and concentrated in vacuo. The residue was dissolved in 200mL of boiling methanol/acetonitrile (5:1) containing activated charcoal,filtered, and the filtrate was concentrated in vacuo. The residue wastriturated with methanol, filtered and the solid residue was washed withether and dried to afford 1.6 g (87.4%) of6,11-ethano-12,12-di-(6-methoxypyridin-2-yl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═6--OCH₃-2-Pyridyl; X⁻ ═ClO₄ ⁻).

(f)

A solution of6,11-ethano-12,12-di-(6-methoxypyridin-2-yl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (0.26 g, 0.5 mmol) in 10 mL of 48% HBr was stirred undernitrogen at room temperature for 2 h, and then heated at 90° C. for 4 h,and cooled to room temperature. The mixture was concentrated in vacuo,the residue was treated with boiling methanol containing activatedcharcoal, filtered, and the filtrate was concentrated in vacuo. Theresidue was triturated with acetonitrile, filtered, and the solidproduct was washed with ethyl acetate, ether, and dried (73° C.) invacuo to afford 0.22 g (91.6%) of6,11-ethano-12,12-di-(2oxo-dihydropyridin-6-yl)-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷═H; R⁵ ═R⁶ ═2-oxo-6-dihydropyridyl; X⁻ ═ClO₄ ⁻).

(g)

6,11-Ethano-12,12-di-(2-oxo-dihydropyridin-6-yl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.3 g) was converted to the corresponding chloride bypassing the salt through Dowex® 1×2-200 (Cl⁻) to afford 1.1 g (93.2%) of6,11-ethano-12,12-di-(2-oxo-dihydropyridin-6-yl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═2-oxo-6-dihydropyridyl; X⁻ ═Cl⁻).

EXAMPLE 68 (a)

A mixture of 5 g (0.016 mol) of 10-methoxybenzo[b]quinoliziniumperchlorate in 15 mL of 48% HBr was refluxed with stirring for 18 h,cooled to room temperature, the resulting mixture was filtered, and thesolid residue was washed with cold water to afford 4.3 g of a solidproduct. The above solid was redissolved in warm water and treated withexcess sodium perchlorate, the resulting solid was filtered, washed withcold water and dried to afford 3.4 g (71%) of10-hydroxybenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═10--OH; X⁻ ═ClO₄ ⁻).

(b)

A mixture of 3.4 g (0.011 mol) of 10-hydroxybenzo[b]quinoliziniumperchlorate and 2.72 g (0.017 mol) of 1,1-di(3-furyl)ethylene in 75 mLof acetonitrile was refluxed for 3 h, cooled to room temperature, andthe resulting mixture was concentrated in vacuo. The above residue wastriturated in ether, filtered, and the solid was washed with ether toafford 5.4 g of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furyl; R⁷ ═10--OH;X⁻ ═ClO₄ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (5.3 g, 11.63 mmol) was converted to the correspondingchloride salt by passing the above salt through Dowex® 1×2-200 afterplacing the salt in acetonitrile. The chloride residue obtained wastriturated in water, filtered through celite, and dried in vacuo toafford 3.2 g (94.5%) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-Furyl; R⁷ ═10--OH; X⁻═Cl⁻) as a solid.

EXAMPLE 69 (a)

A mixture of 19.97 g (0.0768 mol) of benzo[b]quinolizinium bromide and15.67 g (0.0768 mol) of 4,5,6,7-tetrahydro-7-(3-furyl)-benzofuran-7-olin 50 mL of ethanol was heated to reflux for 4.5 h, filtered while hot,and the residue was washed with 10 mL of ethanol to yield 14.25 g, afterrecrystallization from water, of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]benzo[b]quinoliziniumbromide (as a mixture of regioisomers), as a white solid.

(b)

Sodium borohydride (6 g) was added to a cold (0° C.) stirring mixture of12.2 g (0.0275 mol) of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]benzo[b]quinoliziniumbromide (regioisomers) in 150 mL of methanol containing 3 g of sodiumbicarbonate and the mixture was stirred for 4.5 h. The mixture wasconcentrated in vacuo, and the residue was partitioned between 200 mL ofwater and 200 mL of methylene chloride. The aqueous layer was extractedwith 200 mL of methylene chloride, the combined organic layer was washedwith 50 mL of water, and concentrated in vacuo to yield 10.5 g of asolid. The solid product was triturated in 30 mL of methylene chloride(insoluble=2.63 g), filtered, and the filtrate was chromatographed onsilica (1.8 L of Hexane/methylene chloride, 4:5) to yield 2.5 g of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]-1,4,5,6,11,11a-hexahydrobenzo[b]quinolizinebromide (pure isomer A), m.p. 177°-178° C.

The 2nd regioisomer was eluted with ethyl acetate/methylene chloride (2L) to afford 3 g of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]-1,4,5,6,11,11a-hexahydrobenzo[b]quinolizinebromide (pure isomer B), m.p. 200° C. (d).

(c)

A mixture of 370 mg of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]-1,4,5,6,11,11a-hexahydrobenzo[b]quinolizinebromide (pure regioisomer A), 400 mg of mercuric acetate in 25 mL of 10%acetic acid in water was stirred and heated at 100° C. for 1 h. Themixture was filtered hot, the residue was washed with 10 mL of water,and the filtrate was treated with excess sodium perchlorate. The solidproduct was filtered, and the solid was dissolved in methylene chlorideand passed through a silica gel column to yield (from the 2nd fraction)40 mg of6,11[[5',4']-4'-(3-furyl)-4,5,6,7-tetrahydrobenzofuryl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; ##STR59## R⁶ ═3-Furanyl; X⁻═ClO₄ ⁻). (Note that reaction yield rose to 57.5% when 2.2 eq ofHg(OAc)₂ was used).

EXAMPLE 70 (a)

To a suspension of 3.5 g (0.139 mol) of sodium hydride in 120 mL of DMFat 0° C. was added 8 g (0.115 mol) of 1,2,3-triazole in 50 mL of DMFdropwise, and the mixture was allowed to warm to room temperature andstirred for 1 h. The above mixture was cooled to 0° C., and 21.8 g(0.139 mol) of p-methoxybenzyl chloride was added, and the mixture wasallowed to warm to room temperature and stirred for 20 h. The reactionmixture was concentrated in vacuo and the residue was purified bychromatography on silica (hexane/ethyl acetate) to afford 14 g (64.5%)of 1-(p-methoxybenzyl)-1,2,3-triazole.

(b)

To a cooled (-78° C.) 600 mL of THF solution containing 14 g (0.074 mol)of 1-(p-methoxybenzyl)-1,2,3-triazole was added n-butyllithium (2.5M, 30mL, 0.07 mol) dropwise over a 15 min period, and the mixture was stirredat -78° C. for 2 h. The mixture was stirred at -78° C. for 1.5 h, andN-methyl-N-methoxy-urethane (4.5 g, 0.033 mol) in 25 mL of THF was addedand the mixture was stirred at -78° C. for 1 h, and was allowed to warmto room temperature and stirred for 2 h under nitrogen. The abovemixture was quenched with saturated ammonium chloride solution and thelayers were separated. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was triturated with ether andfiltered to afford 10.4 g of1,1-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]ketone. The ether filtratewas purified by chromatography on silica to afford an additional 0.9 gof the above ketone.

(c)

To a suspension of methyl triphenylphosphonium bromide (14.5 g; 0.04mol) in 300 mL of THF was added under nitrogen at -5° C. 2.5Mn-butyllithium (16.2 mL, 0.04 mol) and the mixture was stirred for 1 h.To the above mixture was added1,1-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]ketone (10.9 g, 0.027 mol)in 100 mL of THF and the mixture was stirred for 2 h at room temperatureunder nitrogen. The above mixture was quenched with 10 mL of acetone,and 200 mL of ether was added and the mixture was stirred overnight. Themixture was concentrated in vacuo, and the residue was partitionedbetween water and methylene chloride with stirring. The mixture wasfiltered, the organic filtrate was concentrated in vacuo, and theresidue was purified by chromatography on silica to afford 1.2 g (11%)of 1,1-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]-ethylene (Formula III:R³ ═R⁴ ═H; R⁵ ═R⁶ ═1-p-methoxybenzyl-5-(1,2,3-triazoyl).

(d)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(0.82 g; 2.6 mmol) and1,1-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]-ethylene (1.27 g; 3.16mmol) in 25 mL of nitromethane in a sealed wheaton vial was heated at130° C. for 20 h under nitrogen. The reaction mixture was concentratedin vacuo, the residue was dissolved in boiling methanol/acetonitrilecontaining activated charcoal, filtered, and the filtrate wasconcentrated in vacuo to yield a residue. The above residue was purifiedby chromatography on silica (methylene dichloride/ethylacetate/methanol) to yield a brown foam. The brown foam was dissolved in100 mL of boiling acetonitrile/methanol (1:1) containing activatedcharcoal, filtered, and concentrated in vacuo. The residue wastriturated with 30 mL of isopropanol/methanol (3:1), filtered, and thesolid product was washed with ether and dried to afford 720 mg (38.9%)of6,11-ethano-12,12-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═1-p-methoxybenzyl-5-(1 ,2,3-triazolyl); X⁻ ═PF₆ ⁻), as a solid.

(e)

A solution of 680 mg (0.95 mmol) of6,11-ethano-12,12-di[5-(1-p-methoxybenzyl)-1,2,3-triazolyl]5-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate in 25 mL of trifluoroacetic acid was refluxed undernitrogen for 16 h. After adding 10 mL of methanol, the mixture wasconcentrated in vacuo, the residue was triturated with ethyl acetate,and the solid product was filtered. The solid product was treated with100 mL of boiling isopropanol/methanol/acetonitrile (1:1:1) andcharcoal, filtered, and the filtrated was concentrated in vacuo toafford 320 mg (71.1%) of6,11-ethano-12,12-di-(5-1,2,3-triazolyl)6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═5-(1,2,3-triazolyl); X⁻ ═PF₆ ⁻), as a solid.

6,11-Ethano-12,12-di-(5-1,2,3-triazolyl)6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (320 mg, 0.66 mmol) was convened to thecorresponding chloride salt by passing the above salt through Dowex®1×2-200 (Cl⁻) to afford 150 mg (60%) of6,11-ethano-12.12-di-(5-1,2,3-triazoyl)6,11-dihydrobenzo[b]quinoliziniumChloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═5-(1,2,3-triazolyl);X⁻ ═Cl⁻), as a solid.

EXAMPLE 71 (a)

To a solution of 1-triisoproylsilyl-pyrrole (13.2 g, 0.059 mol) in 250mL of THF at -78° C. was added 10.45 g (0.0587 mol) ofN-bromosuccinamide (NBS), and the mixture was stirred at -78° C. for 3h. The reaction mixture was warmed to room temperature and concentratedin vacuo, and the resulting residue in hexane was stirred overnight. Thehexane solution was filtered through alumina eluting with hexane, theeluate was concentrated in vacuo, and the residue was distilled (b.p.107°-108° C./0.2 mm) to afford 10.4 g (58.4%) of3-bromo-1-triisopropylsilyl-pyrrole.

(b)

To a solution of 3-bromo-1-triisopropylsilyl-pyrrole (10.4 g, 0.0292mol) in 150 mL of THF at -78° C. was added n-butyllithium (2.5M, 12.3mL, 0.031 mol) and the mixture was stirred at -78° C. for 1/2 h. To theabove mixture was added N-methyl,N-methoxy-urethane (1.9 g, 0.014 mol)in 25 mL of THF, the mixture was allowed to warm to room temperature andstirred under nitrogen for 20 h. The mixture was quenched with saturatedsodium bicarbonate solution and the layers were separated. The organiclayer was dried over sodium sulfate, concentrated in vacuo, and theresidue was chromatographed on silica (hexane/ether, 2:1) to afford 4.25g (64.3%) of 1,1-di[3-(1-triisopropylsilyl)-pyrrolyl]-ketone, as an oil.

(c)

To a solution of 1,1-di[3-(1-triisopropylsilyl)-pyrrolyl]-ketone (1 g,2.1 mmol) in 30 mL of THF at room temperature was added methylmagnesiumbromide in ether (3.0M, 9 mmol) and the mixture was stirred for 1/2 h.The above reaction mixture was quenched with 2 mL of saturated sodiumbicarbonate solution. The reaction mixture was diluted with methylenechloride, stirred, passed through a florisil column, and the filtratewas concentrated in vacuo to afford 1.1 g (100%) of1,1-di[3-(1-triisopropylsilyl)-pyrrolyl]-ethylene (Formula III: R³ ═R⁴═H; R⁵ ═R⁶ ═1-triisopropylsilyl-3-pyrrolyl).

(d)

A reaction mixture containing benzo[b]quinolizinium perchlorate (0.59 g;2.11 mmol) and 1,1-di[3-(1-triisopropylsilyl)-pyrrolyl]-ethylene (1.1 g;2.3 mmol) in 50 mL of nitromethane was refluxed for 1/2 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas dissolved in 10 mL of methanol and concentrated in vacuo. Theresulting bright yellow solid was triturated with methanol, filtered andwashed with ether to afford 1.25 g (79.1%) of6,11-ethano-12,12-di[3-(1-triisopropylsilyl)-pyrrolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═1-triisopropylsilyl-3-pyrroyl; X⁻ ═ClO₄ ⁻), as a yellow solid.

(e)

To a solution of 1.22 g (1.62 mmol) of6,11-ethano-12,12-di[3-(1-triisopropylsilyl)-pyrrolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 50 mL of methylene chloride was added tetrabutylammoniumfluoride (2.8 mL, 3.08 mmol) and the mixture was stirred at roomtemperature under nitrogen for 15 min. The solid precipitate wasfiltered, washed with methylene chloride, ether, acetonitrile, methylenechloride, and hexane and dried in vacuo at 50° C. to afford 0.65 g of6,11-ethano-12,12-di(3-pyrrolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H;R⁵ ═R⁶ ═3-pyrrolyl; X⁻═ClO₄ ⁻) as a solid.

(f)

6,11-ethano-12,12-di(3-pyrrolyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (600 mg, 1.5 mmol) was converted to the correspondingchloride salt by passing the above salt through Dowex® 1×2-200 (Cl⁻) toafford 350 mg (69%) of6,11-ethano-12,12-di(3-pyrrolyl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-pyrrolyl; X⁻═Cl⁻), as a solid.

EXAMPLE 72 (a)

To 3-furaldehyde (25.0g, 0.26 mol) in THF (250 mL) at 78° C. was addedethynylmagnesium bromide (572 mL, 0.286, 0.5M THF) at the rate of 10 mLper min. The mixture was slowly warmed to room temperature, stirred for1 h and then poured into a cooled ammonium chloride solution. Themixture was extracted with ethyl acetate, and the organic layer wasdried over Na₂ SO₄ and concentrated in vacuo. The residue was distilledat 50°-55° C. and 0.24 mm Hg to afford 1-(3-furyl)-1-hydroxy-2-propyne.

(b)

To a mixture of 1-(3-furyl)-1-hydroxy-2-propane (20.0 g, 0.163 mol),hexane (200 mL) and THF (25 mL) was added tetrabutylammonium bromide(1.05 g, 0.0032 mol), 50% NaOH (150 mL) and then diethylsulfate (30.0g,0.195 mol) at 0° C. The mixture was stirred for 3 h at room temperature,poured into ice, and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over Na₂ SO₄ and concentrated invacuo. The residue was distilled at 70°-84° C. and (10 mm Hg) to afford1-(3-furyl)-1-ethoxy-2-propyne.

(c)

To a mixture of benzo[b]quinolizinium hexafluorophosphate (1.69 g,0.0055 mol), 1-(3-furyl)-1-ethoxy-2-propyne (1.0 g, 0.0066 mol) and THF(25 mL) was added potassium t-butoxide (0.06 g, 0.00055 mol) (forms1-(3-furyl)-1-ethoxyallene in situ). The mixture was heated to refluxfor 10 min, additional potassium t-butoxide (0.06 g) was added and themixture was refluxed for 1 h. Nitromethane (5.0 mL) was added and themixture was refluxed for another 1 h, cooled and the solvent was removedin vacuo. Ether was added to the residue, the mixture was cooled to 0°C. and the solid thus formed was collected by filtration. The solid wasdissolved in ethyl acetate (150 mL), heated to reflux, cooled to roomtemperature and filtered to remove recovered starting material (0.42 g).The filtrate was concentrated in vacuo and the residue was purified bycolumn chromatography on silica eluting with 10% methanol/CH₂ Cl₂. Thepurified product was recrystallized from hot isopropanol (3×) to afford0.173 g of12-(3-furyl)-12-ethoxy-13-methylidene-6-,11-ethano-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate. (Formula I: R¹ ═R² ═R⁷ ═H; R⁵ ═OC₂ H₅ ; R⁶═3-furyl; R³ and R⁴ together=methylidene; X⁻ ═PF₆ ⁻), as a singlegeometric isomer.

EXAMPLE 73

To a solution of 6.5 g (23.6 mmol) of 10-hydroxybenzo[b]quinolizi niumbromide in 400 mL of methylene chloride/pyridine (1:1) was added 100 mgof DMAP and 50 mL of acetic anhydride and the resulting reaction mixturewas stirred under argon at room temperature for 2 h. The reactionmixture was concentrated in vacuo. The residue was suspended in 2:1 10%NaClO₄ /CH₂ Cl₂ (300 mL) and sonicated. The solid was collected byfiltration to afford 4.3 g (55.9%) of 10-acetoxybenzo[b]quinoliziniumperchlorate.

The above 10-acetoxybenzo[b]quinolizinium perchlorate (3.3 g) wasdissolved in 500 mL of water, the solution was boiled, and filtered. Tothe filtrate was added 100 mL of 30% sodium perchlorate solution and themixture was chilled. The precipitated solid was isolated by filtrationand dried in vacuo to afford 1.9 g of 10-acetoxybenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═R² ═H; R⁷ ═10--OAc; X⁻ ═ClO₄ ⁻). Thefiltrate was extracted with methylene chloride (3×100 mL), the organiclayer was dried and concentrated to yield an additional 0.32 g of thedesired acetate perchlorate.

EXAMPLE 74 (a)

A mixture of 9.4 g (60 mmol) of o-methoxybenzyl chloride and2-(1,3-dioxolan-2-yl)pyridine in sulfolane (6 mL) was heated at 80° C.for 5 h, cooled to room temperature, and was allowed to stand overnight.The mixture was poured into 100 mL of ethyl acetate and the reactionmixture was stirred for 30 min. A gummy precipitate was isolated bydecanting ethyl acetate and triturated with ethyl acetate (2×). Thegummy product was dissolved in 100 mL of water, filtered, and treatedwith 150 mL of hot aqueous potassium hexafluorophosphate solution. Thesolid salt was isolated by filtration, washed successively with hotwater and ether, and dried to afford 7.4 g (29.6%) of1-(o-methoxybenzyl)-2(1,3-dioxolan-2-yl)pyridinium hexafluorophophate(Formula VIII: R¹ ═R² ═H; R⁷ ═2'--OCH₃ ; X⁻ ═PF₆ ⁻).

(b)

To 50 g of polyphosphoric acid heated to 95° C. in an oil-bath was addedwith stirring 5 g (12 mmol) of1-(o-methoxybenzyl)-2(1,3-dioxolan-2-yl)pyridinium hexafluorophosphateand the resulting reaction mixture was heated at this temperature withstirring under nitrogen for 5 h. The mixture was cooled to 40° C., and125 mL of water was added followed by an additional 125 mL of water. Theresulting mixture was cooled to room temperature, potassiumhexafluorophosphate (5 g, 27 mmol) was added, the precipitated solid wasisolated by filtration, and the desired salt was washed successivelywith water and ether and then dried to afford 3.2 g (74.9 g) of7-methoxybenzo[b]quinolizinium hexafluorophosphate (Formula II: R¹ ═R²═H; R⁷ ═7--OCH₃ ; X⁻ ═PF⁻ ₆).

EXAMPLE 75 (a)

Following a procedure similar to that described in Example 45, partsa-d, it is contemplated that there can be prepared9-trichlromethylbenzo[b]quinolizinium hexafluorophosphate fromp-trichloromethylbenzoyl chloride.

(b)

Following a procedure similar to that described in Example 77, partsa-b, it is contemplated that there can be prepared4-bromobenzo[b]quinolizinium perchlorate from o-bromobenzyl alcohol, and6-bromo-2-pyridine carboxyaldehyde.

EXAMPLE 76 (a)

A mixture of 47.6 g (0.289 mol) of p-chlorobenzyl chloride and 45 g(0.298 mol) of 2-(1,3-dioxolan-2-yl)-pyridine in 30 mL of sulfolane washeated on a steam bath for 4 hr. After adding an additional 4 g ofp-chlorobenzyl chloride, the reaction mixture was heated on a steam bathfor 12 h and poured into 300 mL of ethyl acetate. Ethyl acetate wasdecanted, and an additional 200 mL of ethyl acetate was added to theresidue with stirring (20 min) and decanted to remove excess2-(1,3-dioxolan-2-yl)-pyridine and p-chlorobenzyl chloride. The ethylacetate wash was repeated and then the brown residue was washed with 300mL of ether to afford 92 g of1-(p-chlorobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium chloride (Formula VI:R¹ ═R² ═H; R⁷ ═4-Cl; Z⁻ ═Cl⁻).

(b)

A mixture of 1-(p-chlorobenzyl-2-(1,3-dioxolan-2-yl)-pyridinium chlorideand 300 mL of 48% HBr was heated at 100° C. for 24 h, cooled,concentrated in vacuo, and poured into 50 g of ice. The resulting tansolid was filtered to afford 7.9 g of 9-chlorobenzo[b]quinoliziniumchloride (Formula II: R¹ ═R² ═H; R⁷ ═9-Cl; X⁻ ═Cl⁻).

The aqueous layer was treated with sodium perchlorate solution in waterand the resulting solid was cooled and filtered to afford 7.9 g (9%) of9-chlorobenzo[b]quinolizinium perchlorate (Formula H: R¹ ═R² ═H; R⁷═9--Cl; X⁻ ═ClO₄ ⁻).

EXAMPLE 77 (a)

To a mixture of 28.3 g (0.15 mol) of o-bromobenzyl alcohol in 1 L ofether cooled to -20° C. was added in portions 32.5 mL (0.32 mol) ofn-butyllithium (10M) in hexane over a 20 min period and the reactionmixture was stirred 1 h.

The above reaction mixture was cooled to -20° C., 19.9 g (0.165 mol) of6-methyl-2-pyridinecarboxaldehyde was added to the mixture, and theresulting reaction mixture was allowed to warm to room temperature.After 1 h, saturated ammonium chloride solution was added to themixture. The diol was extracted with ethyl acetate, washed with brine,the ethyl acetate phase was dried over sodium sulfate, and the solventwas removed in vacuo to afford 21.9 g (70.5%) of2-[1-hydroxy-(2'-hydroxymethyl)-benzyl]-6-methyl-pyridine (Formula X: R¹═6--CH₃ ; R² ═R⁷ ═H).

(b)

To a mixture of 10.34 g (0.05 mol) of2-[1-hydroxy-(2'-hydroxymethyl)-benzyl]-6-methyl-pyridine in 200 mL ofbenzene heated to 80° C. was added in one portion 50 g (0.176) oftrifluoromethanesulfonic anhydride, and the reaction mixture was allowedto react at 60° C. for 10 min, and then allowed to cool to roomtemperature. The reaction mixture was concentrated in vacuo and theresidue was purified by chomatography on silica eluting with 9%methanol/chloroform to yield a pale yellow solid. This solid wasdissolved in water and reacted with excess sodium perchlorate. The solidproduct was filtered, washed with water, and dried to afford 5.54 g(combined yield 37%) of 4-methylbenzo[b]quinolizinium perchlorate(Formula II: R¹ ═4--CH₃ ; R² ═R⁷ ═H; X⁻ ═ClO₄ ⁻), as a yellow solid,m.p. 160°-165° C.

EXAMPLE 78

To 8.22 g (0.0316 mol) of benzo[b]quinolizinium bromide was added withcooling in an ice-bath 24.4 mL (0.474 mol) of bromine and the reactionmixture was allowed to stand at room temperature 24 h. The reactionmixture was poured into ethyl acetate, refrigerated at -15° C. for 24 h,and the resulting solid was filtered. The solid product was washed withethyl acetate, dissolved in boiling methanol/acetone (1:1), refluxed for15 min, and the solution was concentrated in vacuo to yield a whitesolid. The solid was stirred at room temperature with 400 mL of waterand sodium acetate for 24 h and filtered. The red filtrate was treatedwith sodium perchlorate (15 g) and a resulting yellow solid wasfiltered. The solid product was dissolved in methylene chloride/ethylacetate (1:1) and the methylene chloride was distilled (1/2 of theoriginal volume) in vacuo. The reaction mixture was cooled and the solidproduct was filtered to afford 3.6 g (32.3%) of10-bromobenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═10--Br; X⁻ ═ClO₄ ⁻), m.p. 112°-115° C.

EXAMPLE 79 (a)

To a mixture of 15.0 g (0.098 mol) of 3,4-methylenedioxybenzyl alcoholin 250 mL of ether cooled to -20° C. was added in portions 21.1 mL(0.211 mol) of n-butyllithium (10M) in hexane over 10 min period, andthe reaction mixture was allowed to warm to room temperature and stirred1 h. The above reaction mixture was cooled to -20° C., 11.18 mL (0.117mol) of 2-pyridinecarboxaldehyde was added to the mixture, and theresulting reaction mixture was allowed to warm to room temperature.Ammonium chloride solution (70 mL) was added to the mixture and themixture was extracted with methylene chloride (3×150 mL). The organiclayer was washed with brine, dried over sodium sulfate, andconcentrated. The diol was purified by chomatography on silica elutingwith ethyl acetate/hexane (9:1). The diol was triturated with ether andfiltered to afforded 8.8 g (34.7%) of2-[1-hydroxy-(6'-hydroxymethyl-2',3'-methylenedioxy)benzyl]-pyridine(Formula X: R¹ ═R² ═H; R⁷ ═2',3'(--OCH₂ O--), as a white solid, m.p.98°-101° C.

(b)

To a mixture of 2 g (0.0077 mol) of2-[1-hydroxy-(6'-hydroxymethyl-2',3'-methylenedioxy)benzyl]pyridine in80 mL of benzene heated to 50° C. was added in one portion 7.64 g (0.027mol) of trifluoromethanesulfonic anhydride, and the mixture was allowedto cool to room temperature and stirred for 30 min. The reaction mixturewas concentrated in vacuo and the residue was purified by chomatographyon silica eluting with 10% methanol/methylene chloride to yield a redsolid. This solid was dissolved in water to react with the excess sodiumperchlorate. The solid product was filtered, washed with water, anddried to afford 0.069 g (2.4%) of9,10-methylenedioxybenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R²═H; R⁷ ═2',3'(--OCH₂ O--); X⁻ ═--ClO₄ ⁻), as an orange solid, m.p.220°-224° C.

EXAMPLE 80 (a)

To a mixture of 3.59 g (0.019 mol) of o-bromobenzyl alcohol in 100 mL ofether cooled to -20° C. was added in portions 4.1 mL (0.0412 mol) ofn-butyllithium (10M) in hexane over a 6 min period, and the reactionmixture was stirred 20 min. The above reaction mixture was cooled to -20° C., 3 g (0.021 mol) of 3-methoxy-pyridine-2-carboxaldehyde in 5 mL ofTHF was added in one portion to the mixture, and the resulting reactionmixture was allowed to warm to room temperature and stirred for 20 min.Ammonium chloride solution (30 mL) was added to the mixture and themixture was extracted with ethyl acetate (3×50 mL). The organic layerwas washed with brine, dried over sodium sulfate, and concentrated. Thediol was triturated with 100 mL of ether, filtered, and purified bychomatography on silica eluting with 4% methanol/hexane. The solvent wasconcentrated in vacuo to afford 0.68 g (14.5%) of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-methoxypyridine (Formula X: R¹═3--OCH₃ ; R² ═R⁷ ═H), as a white solid, m.p.138°-140° C.

(b)

To a mixture of 0.61 g (0.00248 mol) of2-[1-hydroxy-(2'-hydroxymethyl)-benzyl]-3-methoxypyridine in 50 mL ofbenzene heated to 50° C. was added in one portion 2.11 g (0.0074 mol) oftrifluoromethanesulfonic anhydride, and the mixture was allowed to coolto room temperature and stirred for 30 min. The reaction mixture wasconcentrated in vacuo and the residue was purified by chomatography onsilica eluting with 5% methanol/methylene chloride and 10%methanol/methylene chloride. The second fraction was concentrated invacuo, the residue was dissolved in hot water (20 mL), heated to reflux,and reacted with the excess sodium perchlorate. The solid product wasfiltered, washed with water, and dried to afford 0.27 g (18.2%) of1-methoxybenzo[b]quinolizinium perchlorate (Formula II: R¹ ═1--OCH₃ ; R²═R⁷ ═H; X⁻ ═ClO₄ ⁻), as a yellow solid, m.p. 143°-145° C.

EXAMPLE 81 (a)

A mixture of 2-(1,3-dioxolan-2-yl)-pyridine (48.7g; 0.322 mol) andp-bromobenzyl-bromide (80.52 g; 0.322 mol) in 60 mL of sulfolane washeated on a steam-bath (after 1 h a red precipitate forms) for 3 h.After cooling, 300 mL of ethyl acetate was added to the mixture,sonicated for 30 min, filtered, and the solid was dried to yield 110 g(85.2%) of 1-(p-bromobenzyl)-2-(1,3-dioxolan-2-yl) pyridinium bromide(Formula VI: R¹ ═R² ═H; R⁷ ═4--Br; Z⁻ ═Br⁻).

(b)

A mixture of 55 g (0.137 mol) of1-(p-bromobenzyl)-2-(1,3-dioxolan-2-yl)pyridinium bromide and 300 g of48% HBr was heated to 100° C. for 24 h and then cooled. The reactionmixture was poured into 250 g of ice and the resulting yellowprecipitate was filtered and dried in vacuo (at 45° C.) to afford 32.85g (70.8%) of 9-bromobenzo[b]quinolizinium bromide (Formula II: R¹ ═R²═H; R⁷ ═9--Br; X⁻ ═Br⁻).

EXAMPLE 82 (a)

A mixture of 2-(1,3-dioxolan-2-yl) pyridine (36.4 g, 0.24 mol),4-nitrobenzylbromide (51.84 g, 0.24 mol) and sulfolane (50 mL) washeated on a steam bath for 10 h. The mixture was cooled, ethyl acetate(300 mL) was added and the mixture was heated to 60° C. A precipitateformed which was collected by filtration to afford1-(p-nitrobenzyl)-2-1,3-dioxolan-2-yl) pyridinium bromide (Formula VI:R¹ ═R² ═H; R⁷ ═4--NO₂ ; Z⁻ ═Br⁻).

(b)

To a mixture of polyphosphoric acid (250 mL) and methanesulfonic acid(55 mL) heated to 100° C. with stirring was added 71 g (0.193 mol) of1-(p-nitrobenzyl)-2-(2'-1',3'-dioxolane)pyridinium bromide and theresulting mixture was heated to 110° C. for 4 h and cooled. The reactionmixture was poured into 500 g of ice, activated charcoal was added tothe mixture, filtered, and sodium perchlorate solution added. Themixture was extracted with methylene chloride (2×500 mL), and theorganic layer was concentrated to afford 5.2 g (8.3%) of9-nitrobenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═9--NO₂ ; X⁻ ═ClO₄ ⁻), as a brown solid.

EXAMPLE 83 (a)

To a mixture of 12.49 g (0.0621 mol) of o-bromo-m-methylbenzyl alcoholin 400 mL of ether cooled to -20° C. was added in portions 13.3 mL(0.1335 mol) of n-butyllithium (10M) in hexane over a 20 min period, andthe reaction mixture was allowed to warm to room temperature and stirred1 h. The above reaction mixture was cooled to -20° C., 14.63 g (0.136mol) of pyridine-2-carboxaldehyde in 50 mL of ether was added to themixture over an 1 h period (the mixture turns purple), and the resultingreaction mixture was allowed to warm to room temperature and stirred for1 h. Ammonium chloride solution (100 mL) and 200 mL of ethyl acetatewere added to the mixture with stirring, and the mixture was extractedwith ethyl acetate (2×200 mL). The combined organic layer was washedwith brine, dried over sodium sulfate, and concentrated. The diol wastriturated with 100 mL of ether, filtered, and the solid product waswashed with hexane (yield: 6.6 g; 46%) to afford2-[1-hydroxy-(2'-hydroxymethyl-6'-methyl)-benzyl]-pyridine (Formula X:R¹ ═R² ═H; R⁷ ═6'--CH3), as a pale yellow solid, m.p. 129°-132° C.

(b)

To a mixture of 3 g (0.013 mol) of2-[1-hydroxy-(2'-hydroxymethyl-6'-methyl)-benzyl]-pyridine in 100 mL ofbenzene heated to 40° C. was added in one portion 12.96 g (0.0458 mol)of trifluoromethanesulfonic anhydride, and the mixture was allowed tocool to room temperature and stirred for 30 min. The reaction mixturewas concentrated in vacuo and the residue (a red oil) was purified bychomatography on silica eluting with 9% methanol/methylene chloride. Theeluate was concentrated in vacuo, the residue was dissolved in water (60mL), heated to reflux, and reacted with 3 g of sodium perchlorate withstirring. The yellow solid product was filtered, washed with water, anddried to afford 0.926 g (24.4%) of 10-methylbenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═R² ═H; R⁷ ═10--CH₃ ; X⁻ ═ClO₄ ⁻), as a paleyellow solid, mp 163°-166° C.

EXAMPLE 84 (a)

To a mixture of 10 g (0.059 mol) of 2,5-dimethoxybenzyl alcohol in 250mL of ether cooled to -20° C. was added in portions 12.75 mL (0.127 mol)of n-butyllithium (10M) in hexane over a 10 min period, and the reactionmixture was allowed to warm to room temperature and stirred 1 h. Theabove reaction mixture was cooled to -20° C., 7.58 g (0.07 mol) ofpyridine-2-carboxaldehyde was added to the mixture, and the resultingreaction mixture was allowed to warm to room temperature (a brownprecipitate formed) and stirred for 1 h. Ammonium chloride solution (60mL) was added, the mixture was extracted with ethyl acetate, thecombined organic layer was washed with brine, dried over sodium sulfate,and concentrated. The diol was purified by chomatography on silicaeluting with ethyl acetate/hexane (9:1) to afford 1.7 g (10.5%) of2-[(2',5'-dimethoxy-6'-hydroxymethyl)benzyl]pyridine (Formula X: R¹ ═R²═H; R⁷ ═2',5-(OCH₃)₂), as a white solid, m.p. 102°-104° C.

(b)

To a mixture of 1.25 g (0.045 mol) of2-[(2',5'-dimethoxy-6'-hydroxymethyl)-benzyl]pyridine in 60 mL ofbenzene heated to 50° C. was added in one portion 4.5 g (0.0159 mol) oftrifluoromethanesulfonic anhydride, and the mixture was allowed to coolto room temperature and stirred for 30 min. The reaction mixture wasconcentrated in vacuo and the residue (an oil) was purified bychomatography on silica eluting with 10% methanol/methylene chloride.The eluate was concentrated in vacuo, the residue was dissolved in water(30 mL), heated to reflux, and reacted with excess sodium perchloratewith stirring and then cooled (using ultrasound and ice). The orangesolid product was filtered, washed with water (4 mL), and dried in vacuoto afford 0.42 g (27.6%) of 7,10-dimethoxybenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═R² ═H; R⁷ ═7,10-(OCH₃)₂ ; X⁻ ═ClO₄ ⁻), asan orange solid, m.p.235°-240° C.

EXAMPLE 85

A mixture of 3-methoxybenzylchloride (5.0 g, 0.032 mol) and2-(1,3-dioxolan-2-yl) pyridine (5.0 g, 0.032 mol) was stirred at roomtemperature for 5 days, then at reflux for 1 day. HCl (50 mL) was addedand the mixture was heated for 3 more days. The mixture was cooled, thesolvent was removed in vacuo and the residue was diluted with water andtreated with KPF₆ (7.0 g) in water. A precipitate formed, which wascollected by filtration. The solid product was purified by columnchomatography on silica eluting with acetonitrile/CH₂ Cl₂ (1/3),followed by slurrying the product in hot methanol and then collectingthe product by filtration to afford 1.0 g of8-methoxybenzo[b]quinolizinium hexafluorophosphate (Formula II: R¹ ═R²═H; R⁷ ═8--OCH₃ ; X⁻ ═PF₆ ⁻).

Following procedures similar to those described in Example 42, partsa-b, but substituting an appropriately substituted 5- or 6-memberedmonocyclic aromatic heterocyclic halide, or 5- or 6-membered monocyclicnonaromatic heterocyclic halide, or 9- or 10-membered bicyclic aromaticheterocyclic halide for 3-bromopyridine in part a, it is comtemplatedthat the following olefins of Formula III, illustrated in Table 1 can beprepared.

                                      TABLE 1                                     __________________________________________________________________________     ##STR60##                                     III                            Example Number                                                                         R.sup.3                                                                         R.sup.4                                                                         R.sup.5           R.sup.6                                        __________________________________________________________________________    86       H H                                                                                ##STR61##                                                                                       ##STR62##                                     87       H H                                                                                ##STR63##                                                                                       ##STR64##                                     88       H H                                                                                ##STR65##                                                                                       ##STR66##                                     89       H H                                                                                ##STR67##                                                                                       ##STR68##                                     90       H H                                                                                ##STR69##                                                                                       ##STR70##                                     91       H H                                                                                ##STR71##                                                                                       ##STR72##                                     92       H H                                                                                ##STR73##                                                                                       ##STR74##                                     93       H H                                                                                ##STR75##                                                                                       ##STR76##                                     94       H H                                                                                ##STR77##                                                                                       ##STR78##                                     95       H H                                                                                ##STR79##                                                                                       ##STR80##                                     96       H H                                                                                ##STR81##                                                                                       ##STR82##                                     97       H H                                                                                ##STR83##                                                                                       ##STR84##                                     98       H H                                                                                ##STR85##                                                                                       ##STR86##                                     99       H H                                                                                ##STR87##                                                                                       ##STR88##                                     100      H H                                                                                ##STR89##                                                                                       ##STR90##                                     101      H H                                                                                ##STR91##                                                                                       ##STR92##                                     102      H H                                                                                ##STR93##                                                                                       ##STR94##                                     103      H H                                                                                ##STR95##                                                                                       ##STR96##                                     104      H H                                                                                ##STR97##                                                                                       ##STR98##                                     105      H H                                                                                ##STR99##                                                                                       ##STR100##                                    106      H H                                                                                ##STR101##                                                                                      ##STR102##                                    107      H H                                                                                ##STR103##                                                                                      ##STR104##                                    107a     H H                                                                                ##STR105##                                                                                      ##STR106##                                    107b     H H                                                                                ##STR107##                                                                                      ##STR108##                                    107c     H H                                                                                ##STR109##                                                                                      ##STR110##                                    107d     H H                                                                                ##STR111##                                                                                      ##STR112##                                    107e     H H                                                                                ##STR113##                                                                                      ##STR114##                                    __________________________________________________________________________

EXAMPLES 108 a-b

Following procedures similar to those described in Example 64, parts b,and c, but substituting an appropriate halide forp-methoxybenzylchloride in part b, it is contemplated that there can beprepared the following olefins of the Formula III.

(a)

1,1-Di[1-(methyl-3-pyrazolyl]ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═1-methyl-3-pyrazolyl)

(b)

1,1-Di[1-(benzyl)-3-pyrazolyl]ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═1-benzyl-3-pyrazolyl)

EXAMPLES 109 a-b

Following procedures similar to those described in Example 70, parts a,b, and c, but substituting an appropriate halide forp-methoxybenzylchloride in part a, it is contemplated that there can beprepared the following olefins of the Formula III.

(a)

1,1-Di[1(4-methylbenzyl)-5-(1,2,3-triazolyl)]ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═1-(4-methylbenzyl)-5-(1,2,3-triazolyl))

(b)

1,1-Di[1(4-chlorobenzyl)-5-(1,2,3-triazolyl)]ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═1-(4-chlorobenzyl)-5-(1,2,3-triazolyl))

EXAMPLES 110 a-b

Following procedures similar to those described in Example 46, part a,but substituting an appropriately substituted benzophenone derivativefor 3 3'-bis (trifluoromethyl) benzophenone, it is contemplated that thefollowing olefins of the Formula III can be prepared.

(a)

1,1-Di(3-trichloromethylphenyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═3-trichloromethylphenyl)

(b)

1,1-Di(3-hydroxyphenyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═3-hydroxyphenyl)

EXAMPLE 111 (a-b)

Following procedures similar to those described hereinabove, or byutilizing procedures which are known in the art, the following knowncompounds (Examples 111 (a)-(b)) were prepared and, unexpectedly, theywere found to bind to the PCP receptor and are thus useful in thetreatment or prevention of neurodegenerative disorders or neurotoxicinjuries.

(a)

6,11-Ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate.

(b)

6,11-Ethano-12-phenyl-12-(4-morpholinyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate.

Following procedures similar to those described in Example 42 (c), butsubstituting an appropriately substituted olefin of the Formula III for1,1-di(3-pyridyl)ethylene and an appropriately substitutedbenzo[b]quinolizinium salt of the Formula II for benzo[b]quinoliziniumperchlorate it is contemplated that the following compounds of theFormula I illustrated in Table 2 can be prepared.

                                      TABLE 2                                     __________________________________________________________________________     ##STR115##                               I                                   Ex-                                                                           ample                                                                         Num                                                                           ber R.sup.1                                                                            R.sup.2                                                                         R.sup.3                                                                         R.sup.5           R.sup.4                                                                         R.sup.6           R.sup.7 X.sup.-            __________________________________________________________________________    112 H    H H                                                                                ##STR116##       H                                                                                ##STR117##       10-OC(O)CH.sub.3                                                                      ClO.sub.4                                                                     .sup.-             113 H    H H                                                                                ##STR118##       H                                                                                ##STR119##       7-OCH.sub.3                                                                           PF.sub.6                                                                      .sup.-             114 H    H H                                                                                ##STR120##       H                                                                                ##STR121##       9-CCl.sub.3                                                                           PF.sub.6                                                                      .sup.-             115 4-Br H H                                                                                ##STR122##       H                                                                                ##STR123##       H       ClO.sub.4                                                                     .sup.-             116 H    H H                                                                                ##STR124##       H                                                                                ##STR125##       9-Cl    Cl.sup..sup.-      117 4-CH.sub.3                                                                         H H                                                                                ##STR126##       H                                                                                ##STR127##       H       ClO.sub.4                                                                     .sup.-             118 H    H H                                                                                ##STR128##       H                                                                                ##STR129##       10-Br   ClO.sub.4                                                                     .sup.-             119 H    H H                                                                                ##STR130##       H                                                                                ##STR131##       9,10-OCH.sub.2                                                                        ClO.sub.4                                                                     .sup.-             120 1-OCH.sub.3                                                                        H H                                                                                ##STR132##       H                                                                                ##STR133##       H       ClO.sub.4                                                                     .sup.-             121 H    H H                                                                                ##STR134##       H                                                                                ##STR135##       9-Br    Br.sup.-           122 H    H H                                                                                ##STR136##       H                                                                                ##STR137##       9-NO.sub.2                                                                            ClO.sub.4                                                                     .sup.-             123 H    H H                                                                                ##STR138##       H                                                                                ##STR139##       10-CH.sub.3                                                                           ClO.sub.4                                                                     .sup.-             124 H    H H                                                                                ##STR140##       H                                                                                ##STR141##       7,10-(OCH.sub.3).sub.2                                                                ClO.sub.4                                                                     .sup.-             125 H    H H                                                                                ##STR142##       H                                                                                ##STR143##       8-OCH.sub.3                                                                           PF.sub.6                                                                      .sup.-             126 H    H H                                                                                ##STR144##       H                                                                                ##STR145##       10-OC(O)CH.sub.3                                                                      ClO.sub.4                                                                     .sup.-             127 H    H H                                                                                ##STR146##       H                                                                                ##STR147##       9-CCl.sub.3                                                                           PF.sub.6                                                                      .sup.-             128 4-Br H H                                                                                ##STR148##       H                                                                                ##STR149##       H       ClO.sub.4                                                                     .sup.-             129 4-CH.sub.3                                                                         H H                                                                                ##STR150##       H                                                                                ##STR151##       H       ClO.sub.4                                                                     .sup.-             130 H    H H                                                                                ##STR152##       H                                                                                ##STR153##       9,10-OCH.sub.2                                                                        ClO.sub.4                                                                     .sup.-             131 1-OCH.sub.3                                                                        H H                                                                                ##STR154##       H                                                                                ##STR155##       H       ClO.sub.4                                                                     .sup.-             132 H    H H                                                                                ##STR156##       H                                                                                ##STR157##       9-NO.sub.2                                                                            ClO.sub.4                                                                     .sup.-             133 H    H H                                                                                ##STR158##       H                                                                                ##STR159##       10-CH.sub.3                                                                           ClO.sub.4                                                                     .sup.-             134 H    H H                                                                                ##STR160##       H                                                                                ##STR161##       7,10-(OCH.sub.3).sub.2                                                                ClO.sub.4                                                                     .sup.-             135.sup.(a)                                                                       H    H H                                                                                ##STR162##       H                                                                                ##STR163##       10-OC(O)CH.sub.3                                                                      ClO.sub.4                                                                     .sup.-             136.sup.(b)                                                                       4-Br H H                                                                                ##STR164##       H                                                                                ##STR165##       H       ClO.sub.4                                                                     .sup.-             137.sup.(c)                                                                       H    H H                                                                                ##STR166##       H                                                                                ##STR167##       7,10-(OCH.sub.3).sub.2                                                                ClO.sub.4                                                                     .sup.-             138 4-Br H H 3-HO-Ph           H 3-HO-Ph           H       ClO.sub.4                                                                     .sup.-             139 4-CH.sub.3                                                                         H H 3-CCl.sub.3 -Ph   H 3-CCl.sub.3 -Ph   H       ClO.sub.4                                                                     .sup.-             140 1-OCH.sub.3                                                                        H H                                                                                ##STR168##       H                                                                                ##STR169##       H       ClO.sub.4                                                                     .sup.-             141 4-Br H H                                                                                ##STR170##       H                                                                                ##STR171##       H       ClO.sub.4                                                                     .sup.-             142 4-CH.sub.3                                                                         H H                                                                                ##STR172##       H                                                                                ##STR173##       H       ClO.sub.4                                                                     .sup.-             143 1-OCH.sub.3                                                                        H H                                                                                ##STR174##       H                                                                                ##STR175##       H       ClO.sub.4                                                                     .sup.-             144 H    H H                                                                                ##STR176##       H                                                                                ##STR177##       H       Br.sup.-           145 H    H H                                                                                ##STR178##       H                                                                                ##STR179##       H       Br.sup.-           146 H    H H                                                                                ##STR180##       H                                                                                ##STR181##       H       Br.sup.-           147 H    H H                                                                                ##STR182##       H                                                                                ##STR183##       H       Br.sup.-           148 H    H H                                                                                ##STR184##       H                                                                                ##STR185##       H       Br.sup.-           149.sup.(d)                                                                       H    H H                                                                                ##STR186##       H                                                                                ##STR187##       H       Br.sup.-           150.sup.(e)                                                                       H    H H                                                                                ##STR188##       H                                                                                ##STR189##       H       Br.sup.-           151.sup.(f)                                                                       H    H H                                                                                ##STR190##       H                                                                                ##STR191##       H       Br.sup.-           152.sup.(g)                                                                       H    H H                                                                                ##STR192##       H                                                                                ##STR193##       H       Br.sup.-           153 H    H H                                                                                ##STR194##       H                                                                                ##STR195##       10-Br   ClO.sub.4                                                                     .sup.-             __________________________________________________________________________     .sup.(a) Prepared by treating the compound of Example 112 with                trifluoroacetic acid.                                                         .sup.(b) Prepared by treating the compound of Example 128 in                  dichloroethane with trifluoroacetic acid.                                     .sup.(c) Prepared by treating the compound of Example 134 with                trifluoroacetic acid.                                                         .sup.(d) Prepared by treating the compound of Example 144 with                trifluoroacetic acid.                                                         .sup.(e) Prepared by treating the compound of Example 145 with                trifluoroacetic acid.                                                         .sup.(f) Prepared by treating the compound of Example 147 in                  dichloroethane with trifluoroacetic acid.                                     .sup.(g) Prepared by treating the compound of Example 148 in                  dichloroethane with trifluoroacetic acid.                                

EXAMPLE 154 (a), (b), (c), and (d)

It is contemplated that by treatment of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride of Example 68(c) with heptadecanoyl chloride, propionylchloride, ethylsuccinyl chloride, or hexadecyl succinyl chloride therecan be prepared the following compounds of the Formula I, respectively,

(a)

6,11-Ethano-12,12-di(3-furyl)-10-[OC(O)(CH₂)₁₅ CH₃]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³ ═R⁴═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10-[OC(O)(CH₂)₁₅ CH₃ ]; X⁻ ═Cl⁻).

(b)

6,11-Ethano-12,12-di(3-furyl)-10-[OC(O)C₂ H₅]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³ ═R⁴═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10-[OC(O)C₂ H₅ ]; X⁻ ═Cl⁻).

(c)

6,11-Ethano-12,12-di(3-furyl)-10-[OC(O)(CH₂)₂ C(O)OC₂ H₅]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³ ═R⁴═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10-[OC(O)(CH₂)₂ C(O)OC₂ H₅ ]; X⁻ ═Cl⁻).

(d)

6,11-Ethano-12,12-di(3-furyl)-10-[OC(O)(CH₂)₂ C(O)O(CH₂)₁₅ CH₃]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³ ═R⁴═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10-[OC(O)(CH₂)₂ C(O)O(CH₂)₁₅ CH₃ ]; X⁻ ═Cl⁻).

EXAMPLE 155 (a)

Following a procedure similar to that described in Example 82, partsa-b, but substituting 4-cyanobenzyl bromide for 4-nitrobenzyl bromide itis contemplated that there can be prepared 9-cyanobenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═R² ═H; R⁷ ═9--CN; X⁻ ═ClO₄ ⁻).

(b)

It is contemplated that treatment of 9-cyanobenzo[b]quinoliziniumperchlorate with 1,1-diphenylethylene, following a procedure similar tothat described in Example 42(c), will afford9-cyano-6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═9--CN; X⁻═ClO₄ ⁻).

(c)

It is contemplated that the treatment of the compound of Example 155(b)with aqueous sodium hydroxide containing about 6-12% of H₂ O₂ withafford9-carboxy-6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═9--CO₂ H;X⁻ ═ClO₄ ⁻).

(d) and (e)

It is contemplated that treatment of the compound of Example 155(c) witheither propanol or hexadecanol in the presence ofdicyclohexylcarbodiimide will afford, respectively,9-[C(O)Opropyl]-6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Example 155(d) Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶═phenyl; R⁷ ═9--C(O)Opropyl; X⁻ ═ClO₄ ⁻) and 9-[C(O)O(CH₂)₁₅ CH₃]-6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Example 155(e) Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶═phenyl; R⁷ ═9-[C(O)O(CH₂)₁₅ CH₃ ]; X⁻ ═ClO₄ ⁻).

EXAMPLE 156

It is contemplated that treatment of6,11-ethano-12,12-diphenyl-10-bromo-6,11-dihydrobenzo[b]quinoliziniumperchlorate of Example 153 with diethyl phosphite in the presence of asource of Pd(0) will afford 6,11-ethano-12,12-diphenyl-10-[P(O)(OC₂ H₅)₂]-6,11-dihydrobenzo[b]quinolizinium perchlorate, which can be hydrolyzedwith aqueous hydrochloric acid to afford6,11-ethano-12,12-diphenyl-10-(PO₃ H)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═phenyl; R⁷ ═10--PO₃H; X⁻ ═ClO₄ ⁻).

EXAMPLE 157

A mixture of 10-(SO₃ ⁻)-benzo[b]quinolizinium (0.99 g, 3.47 mmol)(prepared as described in Bradsher and Turner, J. Org. Chem. 1965, 31,565-567), acetonitrile (20 mL) and 1,1-di-(3-furyl)ethylene (0.83 g, 5.2mmol) was refluxed for three days. The solvent was removed in vacuo andthe residue was triturated with ether, filtered and washed with ether.The residue was purified by column chromatography on silica eluting withdichloromethane/methanol (8/2) to afford crude product, which wasrecrystallized from acetonitrite/ethyl acetate, then water to afford0.58 g (40%) of 10-(SO₃⁻)-6,11-ethano-12,12-di(3-furyl)-6,11-dihydrobenzo[b]quinoliziniumFormula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═SO₃ ⁻), m.p. 300° C.(dec).

EXAMPLE 158 (a)

To a cooled (-78° C.) solution of 1-(p-methoxyphenyl)methyl-pyrazole(110 g, 0.582 mol) in 3 L of ether/THF (2:1) was added in portions, 240ml (0.593 mol) of n-butyllithium (2.5M) over a 1 hour period, and themixture was stirred at -78° C. for 1.5 h. To the above mixture was addedat -78° C. N-methyl-N-methoxy-urethane (37.1 g, 0.28 mol), the mixturewas stirred for 1 h at -78° C., then allowed to warm to -10° C. Themixture was quenched with saturated ammonium chloride solution andstirred overnight. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was purified by medium pressureliquid chromatography to afford 48 g (42.8%) of1,1-di[5-(1-(p-methoxy-phenyl)methylpyrazolyl]ketone.

(b)

A solution of 1,1-di[5-(1-(p-methoxyphenyl)methylpyrazolyl]-ketone (43.6g, 0.108 mol) in 250 ml of trifluoroacetic acid was refluxed undernitrogen for 16 hours, cooled to room temperature, and concentrated invacuo. The residue was suspended in methanol/ether (100 ml, 1:3),stirred, and filtered. The filtrate was concentrated in vacuo, theresidue was triturated in methylene chloride, filtered, and the solidwas washed with hexane to afford 16.4 g (93.7%) of1,1-di(5-pyrazolyl)ketone.

(c)

To a solution of 1,1-di(5-pyrazolyl)ketone (3.25 g, 0.02 mol) in 100 mlof DMF cooled to 0° C. was added NaH (1.05 g, 44 mmol), the mixture wasstirred, and methyl iodide (7.1 g, 0.05 mol) was added with stirring.The resulting mixture was stirred for 20 hours allowing the mixture towarm to room temperature. The reaction mixture was concentrated invacuo, the residue was dissolved in ethyl acetate, and the organic layerwas washed with water and brine. The above organic layer was dried andconcentrated in vacuo and the residue was crystallized from ethylacetate and ethyl acetate/methylene chloride/methanol (6:3:1) to afford0.8 g (21%) of 1,1-di[3-(1-methylpyrazolyl]ketone.

(d)

To a solution of potassium t-butoxide (0.63 g, 5.9 mmol) in 50 ml of THFcooled at 0° C. was added methyltriphenyl-phosphonium bromide (2.03 g;5.2 mmol) and the resulting mixture was allowed to warm to roomtemperature with stirring for 1 hour. To the above mixture was added1,1-di[3-(1-methylpyrazolyl]ketone (0.72 g, 3.8 mmol) in 30 ml of THF,and the mixture was stirred for 2 hours at room temperature. The abovemixture was quenched with saturated ammonium chloride solution, stirred,and filtered through a pad of florisil. The filtrate was concentrated invacuo and the residue was purified by chromatography on silica (ethylacetate, ethyl acetate/ether/methanol) to afford 0.6 g (50.7%) of1,1-di3-(1-methylpyrazolyl)]ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶═##STR196##

(e)

A reaction mixture containing 4a-azoniaanthracene perchlorate (0.82 g;2.9 mmol) and 1,1-di[3-(1-methylpyrazolyl)]ethylene (0.6 g; 3.2 mmol) in50 ml of nitromethane was refluxed for 24 h under nitrogen. The reactionmixture was concentrated in vacuo, the residue was dissolved inacetonitrile/methanol (200 ml, 1:1), treated with activated charcoal,filtered, and the filtrate was concentrated in vacuo. The above residuewas triturated in isopropanol/methanol (100 ml, 9:1), filtered, anddried to afford 1.3 g (84.2%) of6,11-ethano-12,12-di[3-(1-methylpyrazolyl)]-6,11-dihydrobenzo[b]-quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR197## X⁻═ClO₄ ⁻), as a solid.

(f)

6,11-Ethano-12,12-di[3-(1-methylpyrazolyl)]-6,11dihydrobenzo[b]quinoliziniumperchlorate (1.3 g, 2.8 mmol) in ethanol/(pyridine/acetic acid/water(55/20/25)) was converted to the corresponding chloride by passing thesalt through DOWEX® 1×2-200-Cl⁻ (water/acetoni-trile, 7.3) to afford0.84 g (74.3%) of6,11-ethano-12,12-di[3-(1-methylpyrazolyl)]-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR198## X⁻═Cl⁻), as a solid.

EXAMPLE 159 (a)

To a suspension of 4 g (0.16 mol) of sodium hydride in 200 ml of DMF at0° C. was added 10 g (0.145 mol) of 1,2,4-triazole in 75 ml of DMFdropwise over a period of 30 minutes, and the mixture was allowed towarm to room temperature and stirred for 1 h. The above mixture wascooled to 0° C., 25 g (0.16 mol) of p-methoxybenzyl chloride was added,the mixture was allowed to warm to room temperature, and stirred for 16h. The reaction mixture was concentrated in vacuo and the residue waspurified by chromatography on silica (hexane/ethyl acetate) to afford21.9 g (64.5%) of 1-(p-methoxybenzyl)-1,2,4-triazole.

(b)

To a cooled (-78° C.) solution containing 14 g (0.074 mol) of1-(p-methoxybenzyl)-1,2,4-triazole (21.9 g, 0.115 mol) in 500 ml of THFwas added n-butyllithium (2.5M, 46.3 ml, 0.115 mol) dropwise over a 15min period. The mixture was stirred at -78° C. for 1.5 h. To the mixturewas added N-methyl-N-methoxy-urethane (6.95 g, 0.052 mol) in 20 ml ofTHF and the mixture was stirred at room temperature for 2 h undernitrogen. The above mixture was quenched with saturated ammoniumchloride solution and was diluted with 200 ml of ethyl acetate. The twolayers were separated. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was triturated in ether,filtered, and washed with hexane to afford 20 g (95.2%) of1,1-di[5-(1-p-methoxybenzyl)-1,2,4-triazolyl]ketone.

(c)

A solution of 1,1-di[5-(1-p-methoxyphenyl)methyl-1,2,4-triazolyl]ketone(10 g, 0.02 mol) in 150 ml of trifluoroacetic acid was refluxed undernitrogen for 18 hours, cooled to room temperature, and concentrated invacuo. The residue was suspended in methylene chloride (200 ml),stirred, and filtered. The residue was washed with methylene chloride,ethyl acetate, and ether to afford 5.4 g of1,1-di[5-(1.2.4-triazolyl)]ketone.

(d)

To a solution of 1,1-di[5-(1,2,4-triazolyl)ketone (5.4 g, 0.032 mol) in200 ml of DMF cooled to 0° C. was added NaH (1.8 g, 72 mmol), and themixture was stirred for 2 hours, and p-methoxybenzyl chloride (12.9 g,0.082 mol) was added with stirring. The resulting mixture was stirredfor 98 hours at room temperature. The reaction mixture was filteredthrough CELITE®, the filtrate was concentrated in vacuo, the residue wasdissolved in ethyl acetate, and the organic layer was washed with waterand brine. The above organic layer was dried and concentrated in vacuoand the residue was crystallized from ethyl acetate and ethylacetate/methylene chloride/methanol (6:3:1) to afford 2.5 g of1,1-di[3-(1-p-methoxybenzyl-1,2,4-triazolyl]ketone.

(e)

To a solution of potassium t-butoxide (0.95 g, 8.4 mmol) in 75 ml of THFat 0° C. was added methyltriphenylphosphonium bromide (2.88 g; 8 mmol)under nitrogen and the mixture was stirred for 1 h at room temperature.To the above mixture was added1,1-di[3-(1-p-methoxybenzyl)-1,2,4-triazolyl]ketone (2.57 g, 6.2 mol) in50 ml of THF and the mixture was stirred for 2 h at room temperatureunder nitrogen. The above mixture was quenched with saturated ammoniumchloride solution, filtered through CELITE®, and the filtrate wasconcentrated in vacuo. The residue was purified by crystallization fromethyl acetate and ethyl acetate/methylene chloride/methanol (6:3:1) toafford 0.9 g (36%) of1,1-di[3-(1-p-methoxybenzyl)-1,2,4-triazolyl]-ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═ ##STR199##

(f)

A reaction mixture containing 4a-azoniaanthracene perchlorate (0.61 g;2.2 mmol) and 1,1 -di[3-(1-p-methoxybenzyl)- 1,2,4-triazolyl]-ethylene(0.85 g; 2.12 mmol) in 25 ml of nitromethane was refluxed for 20 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas dissolved in boiling methanol/acetonitrile containing activecharcoal, filtered, and the filtrate was concentrated in vacuo to yielda residue. The above residue was purified by chromatography on silica(methylene chloride/ethyl acetate/methanol) to yield a brown foam. Theresidue was triturated in water, filtered, and the solid was washed withhexane to afford 0.9 g (62%) of6,11ethano-12,12-di[3-(1-p-methoxybenzyl)-1,2,4-triazolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR200##

(g)

A solution of 700 mg (1.32 mmol) of6,11-ethano-12,12-di[3-(1-p-methoxybenzyl)-1,2,4-triazolyl]-6,11-dihydro-benzo[b]quinoliziniumperchlorate in 50 ml of trifluoroacetic acid was refluxed under nitrogenfor 28 h. The mixture was concentrated in vacuo, the residue trituratedin methanol, and the solid product filtered. The solid was crystallizedfrom ethanol/PAW (1:1) to afford 170 mg (29.3%) of6,11-ethano-12,12-di-[3-(1,2,4-triazolyl)]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR201## X⁻═ClO₄ ⁻).

(h)

6,11-Ethano-12,12-di-[3-(1,2,4-triazolyl)]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (170 mg) was converted to the corresponding chloride salt bypassing the above salt through DOWEX® 1×20-200-C⁻ after placing the saltin acetonitrile. The chloride residue obtained was dried in vacuo toafford 90 mg (88.2%) of6,11-ethano-12,12-di-[3-(1,2,4-triazolyl)]-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR202## as asolid.

EXAMPLE 160 (a)

To a solution of 1 g (3.9 mmol) of 1,1-di(2-chloropyridin-3-yl)methanolin 25 ml of acetone at -30° C. was added CrO₃ (1.17 g, 0.011 mol) inportions, and the mixture was stirred at room temperature for 2 h. Tothe above mixture was added 25 ml of isopropanol and saturated sodiumbicarbonate solution (100 ml) and the mixture was stirred, filteredthrough CELITE®, and washed with 200 ml of chloroform. The combinedfiltrate was washed with brine, the organic layer was dried andconcentrated in vacuo to afford 0.81 g (81%) of1,1-di(2-chloropyridin-3-yl)ketone.

(b)

To 20 ml of methanol was added in portions 0.22 g (9.5 mmol) of sodiumand the mixture was stirred under nitrogen for 0.5 h.1,1-di-(2-chloro)pyridin-3-yl]ketone (0.8 g, 3.16 mmol) in 20 ml ofmethanol was added to the above mixture, and the reaction mixture wasrefluxed under nitrogen for 12 h. The mixture was quenched with 2N HCl(1 ml), concentrated in vacuo, and the residue was dissolved in 100 mlof ethyl acetate. The organic layer was washed with water and brine,dried over sodium sulfate, and concentrated in vacuo. The residue waspurified by chromatography on silica (ethyl acetate/hexane, 1:1) toafford 0.38 g (49.3%) of 1,1-di(2-methoxypyridin-3-yl)ketone.

(c)

To a suspension of 0.26 g (2.34 mmol) of potassium t-butoxide in 20 mlof THF at 0° C. was added methyltriphenylphosphonium bromide (0.86 g;2.34 mmol) and the mixture was stirred at room temperature for 1 h. Tothe above mixture was added 1,1-di(2-methoxypyridin-3-yl)ketone (0.38 g,1.55 mmol) in 10 ml of THF and the mixture was stirred for 1 h at roomtemperature under nitrogen. The above mixture was quenched withsaturated ammonium chloride solution, diluted with ether, filtered, theaqueous layer was extracted with ether, and the combined organic layerwas filtered. The above filtrate was concentrated in vacuo, and theresidue was chromatographed on silica (hexane/ethyl acetate, 2:1) toafford 0.38 g of 1,1-di(2-methoxypyridin-3-yl)ethylene (Formula III: R³═R⁴ ═H; R⁵ ═R⁶ ═ ##STR203##

(d)

A mixture of 0.39 g (1.42 mmol)) of 4a-azoniaanthracene perchlorate and0.38 g (1.55 mmol) of 1,1-di(2-methoxypyridin-3-yl)ethylene in 25 ml ofnitromethane was allowed to reflux under nitrogen for 120 h. The mixturewas cooled, and concentrated in vacuo. The residue was dissolved in 100ml of boiling methanol/acetonitrile (5:1) containing active charcoal,filtered, and the filtrate was concentrated in vacuo. The residue wastriturated in water, filtered and the solid residue washed with waterand ether, and dried to afford 0.13 g (17.5%) of6,11-ethano-12,12-di-(2-methoxypyridin-3-yl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR204## X⁻═ClO₄ ⁻).

EXAMPLE 161 (a)

To a suspension of NaH (0.072 g, 3 mmol) in 20 ml of DMF cooled to 0° C.under argon was added 1,1-di-(pyrazol-4-yl)ketone (0.23 g, 1.4 mmol)with stirring. p-Methoxybenzyl chloride (0.24 g, 1.5 mmol) was added tothe mixture at 0° C. with stirring and the resulting mixture was stirredat room temperature. The reaction mixture was quenched with saturatedammonium chloride solution and the mixture was extracted with ethylacetate (50 ml). The organic layer was washed with water (3×50ml) andbrine (50 ml), dried and concentrated in vacuo to afford 0.4 g of1,1-di[(1-p-methoxybenzyl)pyrazol-4-yl]ketone.

(b)

To a solution of potassium t-butoxide (0.18 g, 1.5 mmol) in 25 ml of THFat 0° C. was added methyltriphenylphosphonium bromide (0.38 g; 1.5 mmol)under nitrogen and the mixture was stirred at room temperature. To theabove mixture was added a solution of1,1-di[(1-p-methoxybenzyl)pyrazol-4-yl]ketone (0.4 g, 1.0 mol) in 5 mlof THF and the mixture was stirred at room temperature under nitrogen.The above mixture was quenched with saturated ammonium chloridesolution, filtered through CELITE®, and the filtrate was concentrated invacuo. The residue was extracted with ethyl acetate (3×20 ml), theorganic layer was washed with brine and dried over sodium sulfate. Theorganic solution was concentrated in vacuo and the residue was purifiedby flash chromatography (ethyl acetate/hexane) to afford 0.16 g of1,1-di[(1-p-methoxybenzyl)-pyrazol-4-yl]ethylene (Formula III: R³ ═R⁴═H; R⁵ ═R⁶ ═ ##STR205##

(c)

A reaction mixture containing 4a-azoniaanthracene perchlorate (0.16 g;0.4 mmol) and 1,1-di[(1-p-methoxybenzyl)-pyrazol-4-yl]-ethylene (0.11 g;0.4 mmol) in 10 ml of acetonitrile was refluxed for 6.5 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas purified by flash chromatography on silica (10% methanol inmethylene chloride) to afford 0.25 g of6.11-ethano-12,12-di[(1-p-methoxy-benzyl)pyrazol-4-yl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR206## X⁻═ClO₄ ⁻), as a solid.

(d)

A solution of 250 mg of6,11-ethano-12,12-di[(1-p-methoxybenzyl)pyrazol-4-yl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 10 ml of trifluoroacetic acid was refluxed under nitrogenfor 8 h. The mixture was concentrated in vacuo, the residue partitionedin 25 ml of water and 20 ml of ethyl acetate. The aqueous layer wasconcentrated in vacuo and the residue was treated with 1 g of sodiumperchlorate in 10 ml of water. The solution was concentrated (to 4 ml)and the resulting solid product was filtered to afford 25 mg of6,11-ethano-12,12-di(pyrazol-4-yl)]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR207## X⁻ ═ClO₄⁻), as a solid, m.p. 160°-170° C.

EXAMPLE 162 (a)

To a mixture of 3-bromofuran (10 g, 0.068 mol) and propargyl alcohol(4.3 ml, 0.074 mol) in 200 ml of TEA was added under argon, CuI (0.26 g,1.4 mmol) and [(C₆ H₅)₃ P]₂ PdCl₂ (1.05 g, 1.4 mmol) and the mixture wasstirred at 0° C. for 2 hours and at room temperature for 72 hours. Thereaction mixture was cooled, decanted, and the solid was washed withTEA. The combined TEA solution was concentrated in vacuo and the residuewas distilled (Kugelrohr distillation) to afford 1.48 g (17.8%) of3-(3-furyl)-2-propynyl alcohol.

(b)

A mixture of 3-(3-furyl)-2-propynyl alcohol (1.45 g, 0.0118 mol), DMAP(1 mg), TEA (2.46 ml, 0.017 mol), and acetic anhydride (1.6 ml, 0.017mol) in 25 ml of methylene chloride was stirred for 1 hour and themixture was poured into cold 1N HCl solution. The mixture was extractedwith ether (3×50 ml), the organic layer was dried over sodium sulfateand concentrated in vacuo. The residue was purified by silica columnchromatography (hexane/ether, 2:1) to afford 1.44 g (57.5%) of3-(3-acetyloxy-1-propynyl)furan as a clear oil.

(c)

To a mixture of 3-(3-acetyloxy-l-propynyl)furan (1.44 g, 8.7 mmol),3-bromofuran (2.55 g, 0.017 mol), and Pd(P(C₆ H₅)₃)₄ (1.0 g, 0.8 mmol)in THF was added added zinc chloride (0.5M in THF, 34 ml, 0.017 mol) andthe mixture was stirred at room temperature for 4 hours. The reactionmixture was concentrated in vacuo and the residue was purified by silicacolumn chromatography (methylene chloride/hexane, 2:1) to afford 1.25 g(85%) of [1,1-di(3-furyl)]-1,2-propadiene (Formula III: R³ and R⁴together form ═CH₂ ; R⁵ ═R⁶ ═3-furanyl) as a pale yellow oil.

(d)

A reaction mixture containing 4a-azoniaanthracene hexafluorophosphate(1.48 g; 4.8 mmol) and 1,1-di(3-furyl)-1,2-propadiene (0.25 g; 7.2 mmol)in 50 ml of nitromethane was refluxed for 4 h under nitrogen. Thereaction mixture was concentrated in vacuo, the residue was trituratedin ether, and the brown residue was filtered. The solid was dissolved inethyl acetate, filtered, and concentrated in vacuo. The resultingresidue was dissolved in isopropanol, cooled, filtered, and the solidwas dried to afford 0.386 g (16.7%) of6,11-ethano-12,12-di(3-furyl)-13-methylene-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R⁷ ═H; R³ and ⁴ together form═CH₂ ; R⁵ ═R⁶ ═3-furanyl; X⁻ ═PF₆ ⁻), as a solid.

EXAMPLE 163

To a solution of 1.0 g (2.2 mmol) of6,11-ethano-12.12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 20 ml of pyridine was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 g, 2.4 mmol) under nitrogen. To the above mixture wasadded stearic acid chloride (1.3 g, 4.4 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo and the residue was purified by silica gel columnchromatography (ethyl acetate, 20% methanol in ethyl acetate). The aboveproduct was dissolved in 20% methylene chloride in methanol and passedthrough AMBERLITE® A-27 column to afford 0.193 g of6,11-ethano-12,12-di(3-furyl)-10-stearyloxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═10--OC(O)(CH₂)₇ CH═CH(CH₂)₇ CH₃) as a solid, m.p. 95°-100° C.

EXAMPLE 164 (a)

To a solution of t-BuLi (216 ml, 1.7M, 0.367 mol) in 1 L of THF at -78°C was added dropwise 1-bromo-2,4,6-trimethyl-benzene (35.6 g, 0.178 mol)over a period of 45 minutes. The mixture was stirred at -78° C. for 1hour, 3-methoxypyridine (15 g, 0.138 mol) was added and then the mixturewas stirred at -23° C. for 3 hours. The above reaction mixture wascooled to -78° C. and 13 g (0.2 mol) of DMF in 25 ml of THF was addedand the mixture was stirred for 1 hour. The reaction mixture wasquenched with 250 ml of brine, the mixture was stirred overnight, anddiluted with 1 L of ether. The aqueous layer was extracted with ethylacetate (1 L), the combined organic layer was dried over potassiumcarbonate, and concentrated in vacuo to afford 7.5 g of3-methoxypyridyl-2-carboxaldehyde.

(b)

To a solution of 4.96 g (0.0265 mol) of 2-bromobenzyl alcohol in 200 mlof ether cooled to -20° C. was added in portions 22.3 ml (55 mmol) of2.5M n-butyllithium in hexane and the resulting mixture was stirred atroom temperature for 2 hours. The reaction mixture was cooled to 0° C.,3.08 g (26.5 mmol) of TMEDA was added. The above reaction mixture wascooled to -30° C., and 4 g (0.029 mol) of3-methoxypyridine-2-carboxaldehyde in 30 ml of THF was added, and theresulting reaction mixture was allowed to warm to 0° C. and quenchedwith 10 ml of water. The resulting diol was filtered, and filtrate wasextracted with ethyl acetate, dried over sodium sulfate, and the solventwas removed in vacuo. The combined residue was triturated in ether/ethylacetate (9:1) and hexane to afford 4 g (64.5%) of2-[1-hydroxy-(2'-hydroxymethyl)-benzyl]-3-methoxy-pyridine (Formula X:R¹ ═3--OCH₃ ; R² ═H; R⁷ ═H).

(c)

A mixture of 4 g (16 mmol) of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-methoxypyridine and 75 ml ofPOCl₃ was heated at 105° C. with stirring for 1 h. The mixture wascooled, concentrated in vacuo, and the residue was dissolved in 50 ml ofwater and 100 ml of 30% sodium perchlorate solution. The resultingmixture was filtered, the solid was washed with water, ethyl acetate,and hexane, and dried to afford 3.5 g (70.7%) of1-methoxy-benzo[b]quinolizinium perchlorate (Formula II: R¹ ═1--OCH₃ ;R² ═R⁷ ═H; X⁻ ═ClO₄ ⁻).

(d)

A reaction mixture containing 1-methoxy-benzo[b]quinoliziniumperchlorate (1.5 g; 4.85 mmol) and 1,1-di(3-furyl)-ethylene (1 g) in 75ml of nitromethane was allowed to reflux under nitrogen with stirringfor 3 hour. The reaction mixture was concentrated in vacuo and theresidue was crystallized from methylene chloride/ethyl acetate/methanol(7:2:1) and charcoal. The solid product was triturated in water anddried to afford 2 g (86.9%) of6,11-ethano-12,12-di(3-furyl)-1-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═1--OCH₃ ; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-furyl; X⁻ ═ClO₄ ⁻) as a solid.

(e)

6,11-Ethano-12,12-di(3-furyl)-1-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (2 g) was converted to the corresponding chloride salt bypassing the above salt through DOWEX® 1×20-200-Cl⁻ after placing thesalt in acetonitrile. The chloride residue obtained was dried in vacuoto afford 0.92 g (53.4%) of6,11-ethano-12,12-di(3-furyl)-1-methoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═1--OCH₃ ; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl;X⁻ ═Cl⁻) as a solid.

EXAMPLE 165

To a solution of 1.0 g (2.2 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 20 ml of pyridine was added DBU (0.37 g, 2.4 mmol) undernitrogen, and to the above mixture was added octanoic acid chloride(0.71 g) and the mixture was stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo and the residue wastriturated with ether, the resulting solid was purified by silica gelcolumn chromatography (10% methanol/ethyl acetate, 20% methanol in ethylacetate). The above product was dissolved in acetonitrile and passedthrough DOWEX® 1×20-200-Cl⁻ column to afford 0.44 g of6,11-ethano-12,12-di(3-furyl)-10-octanoyloxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10--OC(O)C₇H₁₅ ; X⁻ ═Cl⁻) as a solid, m.p. 80°-90° C.

EXAMPLE 166

A mixture of 0.5 g (1.1 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate and CS₂ CO₃ (0.39 g, 1.22 mmol) in 20 ml of acetonitrile wasstirred at room temperature for 10 minutes, and to the above mixture wasadded ethyl succinoyl chloride (0.27 g, 1.6 mmol) and the mixture wasstirred at room temperature. The reaction mixture was concentrated invacuo, the residue was dissolved in acetonitrile, filtered, and thefiltrate was concentrated in vacuo. The above product was dissolved inacetonitrile and passed through DOWEX® 1×20-200-Cl⁻ column to afford0.14 g of6,11-ethano-12,12-di(3-furyl)-10-(3-ethoxycarbonyl)propionyloxy-6,11-dihydrobenzo-[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═10--OC(O)(CH₂)₂ CO₂ Et; X⁻ ═Cl⁻) as a solid, m.p. 120°-124° C.

EXAMPLE 167 (a)

A mixture of ethyl maleic acid (50 g, 0.31 mol) and thionyl chloride (50ml) was heated at 100° C. for 3 hours and the excess thionyl chloridewas removed in vacuo. The residue was distilled to afford 45 g (79.4%)of ethyl maleic chloride as an oil, b.p. 71° C./10 mm.

(b)

To a solution of 0.57 g (1.25 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 25 ml of acetonitrile was added CS₂ CO₃ (0.45 g, 1.38mmol) and the solution was stirred at room temperature for 10 minutes.To the above mixture was added ethyl maleic chloride (0.3 g, 1.38 mmol)and the mixture was stirred at room temperature for 20 hours. Thereaction mixture was filtered and concentrated in vacuo, the residue wastriturated in water, and filtered. The above product was washed withether and dried to afford 0.4 g of6,11-ethano-12,12-di(3-furyl-10-(ethoxycarbonylethenylcarbonyloxy)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═10--OC(O)CH═CH CO₂ Et; X⁻ ═ClO₄ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(3-furyl)-10-(ethoxycarbonylethenylcarbonyloxy)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (0.4 g) was converted to the corresponding chloride bypassing the salt through DOWEX® 1×2-200-Cl⁻ (water/acetonitrile, 7.3) toafford 0.14 g (40%) of 6,11-ethano-12,12-di(3-furyl)-10-(OC(O)CH═CHCO₂Et)-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R¹ ═R² ═R³═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═OC(O)CH═CHCO₂ Et; X⁻ ═Cl⁻), as a solid.

EXAMPLE 168 (a)

A mixture of 1-methoxybenzo[b]quinolizinium perchlorate (1.4 g; 6.1mmol) in 30 ml of 48% HBr was heated at 100° C. for 16 hour. Thereaction mixture was poured into 100 ml of water and 50 ml of sodiumperchlorate was added with stirring. The resulting solid was filteredand dried to afford 1.6 g (88.8%) of 1-hydroxybenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═1--OH; R² ═R³ ═H; X⁻ ═ClO₄ ⁻) as a solid.

(b)

A reaction mixture containing 1-hydroxybenzo[b]quinolizinium perchlorate(1.5 g; 5.07 mmol) and 1,1-di(3-furyl)-ethylene (1.5 g, 9.3 mol) in 50ml of acetonitrile was allowed to reflux under nitrogen with stirringfor 10 hour. The reaction mixture was concentrated in vacuo, the residuewas dissolved in methanol, and filtered. The filtrate was concentratedin vacuo and the residue was crystallized from ether/methylene chloride(100 ml, 2:1). The solid product was filtered and dried to afford 1.7 g(73.9%) of6,11-ethano-12,12-di(3-furyl)-1-hydroxy-6,11-dihydrobenzo[b]-quinoliziniumperchlorate (Formula I: R¹ ═1--OH; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl;X⁻ ═ClO₄ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(3-furyl)-1-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.2 g, 2.6 mmol) was converted to the correspondingchloride salt by passing the above salt through DOWEX® 1×2-200-Cl⁻ afterplacing the salt in acetonitrile. The chloride residue was dried invacuo to afford 0.82 g (75.9%) of6,11-ethano-12,12-di(3-furyl)-1-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═1--OH; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻═Cl⁻) as a solid.

EXAMPLE 169

A mixture of 0.5 g (1.1 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate and CS₂ CO₃ (0.39 g, 1.2 mmol) in 20 ml of acetonitrile wasstirred at room temperature for 10 minutes, and to the above mixture wasadded acetyl chloride (0.13 g, 1.6 mmol) and the mixture was stirred atroom temperature overnight. The reaction mixture was concentrated invacuo, the residue was dissolved in acetonitrile, filtered, and thefiltrate was concentrated in vacuo. The above product was dissolved inacetonitrile and passed through DOWEX® 1×2-200-Cl⁻ column to afford 0.27g of6,11-ethano-12,12-di(3-furyl)-10-acetyloxy-6,11-dihydrobenzo-[b]quinoliziniumchloride (Formula I: R⁻ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═OC(O)CH₃ ;X⁻ ═Cl⁻) as a solid, m.p. 75°-82° C.

EXAMPLE 170

A mixture of 0.4 g (1 mmol) of6,11-ethano-12,12-di(3-furyl)-1-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate and CS₂ CO₃ (0.31 g, 1 mmol) in 20 ml of acetonitrile wasstirred at room temperature for 5 minutes. To the above mixture wasadded acetyl chloride (0.1 g) and the mixture was stirred at roomtemperature. The reaction mixture was concentrated in vacuo, the residuewas triturated in ether, and the solid was filtered. The above productwas dissolved in acetonitrile and passed through DOWEX® 1×2-200-Cl⁻column to afford 0.14 g of6,11-ethano-12,12-di(3-furyl)-1-acetyloxy-6,11-dihydrobenzo-[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═OC(O)CH₃ ;X⁻ ═Cl⁻) as a solid, m.p. 128°-132° C.

EXAMPLE 171 (a)

A solution of KCN (3g, 0.046 mol) in a minimum of water was added to asolution of benzo[b]quinolizinium bromide (10 g; 0.0385 mol) in 200 mlwater. The resulting solid was extracted with an equal volume ofmethylene chloride. The above organic layer was heated and a solution ofbromine (6.4 g) in methylene chloride was added. The resulting yellowsolid was isolated, dissolved in ethanol/water, and the resultingsolution was treated with sodium perchlorate solution. The perchloratesalt was filtered and recrystallized from ethanol to afford 2 g of6-cyano-benzo[b]quinolizinium perchlorate (Formula II: R¹ ═R⁷ ═H; R²═CN; X⁻ ═ClO₄ ⁻) as a solid.

(b)

A reaction mixture containing 6-cyano-benzo[b]quinolizinium perchlorate(1.45 g; 7.07 mmol) and 1,1-di(3-furyl)-ethylene (3 g) in 20 ml ofacetonitrile and 40 ml of ethanol was heated to reflux under nitrogenwhile stirring overnight. The reaction mixture was concentrated invacuo, the residue was dissolved in methylene chloride and purified bysilica gel column chromatography (70% ethyl acetate/30% (55/20/25pyridine/acetic acid water)). Evaporation gave a brown oil whichcrystallized from methanol and was converted to the correspondingchloride salt by passing the compound through DOWEX® 1×2-200-Cl⁻ion-exchange resin. The chloride residue was dried in vacuo andrecrystallized from 2-propanol to afford 0.377 g (13.1%) of6,11-ethano-12,12-di(3-furyl)-6-cyano-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CN; R⁵ ═R⁶ ═3-furyl; X⁻ ═C⁻)as a solid, m.p. 168° C softens.

EXAMPLE 172

To a solution of 0.45 g (1 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 10 ml of DMF was added CS₂ CO₃ (0.65 g, 2 mmol) undernitrogen and the mixture was stirred at room temperature for 10 minutes.To the above mixture was added octyl bromide (0.4 g) and the mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in acetonitrile andfiltered. The filtrate was concentrated in vacuo, the resulting solidwas dissolved in 50 ml of methanol/water/acetonitrile (1:1:1) andtreated with sodium perchlorate (8 g). The mixture was concentrated invacuo, the solid was washed with hexane and ether, and crystallized fromacetonitrile/methanol/ether to afford 0.36 g (63.2%) of 6,11-ethano-12,12-di(3-furyl)-10-octyloxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═O(CH₂)₇CH₃ ; X⁻ ═CIO₄ ⁻) as a solid, m.p. 143°-145° C.

EXAMPLE 173 (a)

To a cooled (-78° C.) solution of 1-(p-methoxyphenyl)methyl-imidazole(9.4 g, 0.05 mol) in 200 ml of ether/THF (1:1) was added in portions, 22ml (0.055 mol) of n-butyllithium (2.5M) over a 1 hour period, and themixture was stirred at -78° C. for 1.5 h. To the above mixture was addedat -78° C. N-methyl-N-methoxy-urethane (3.325 g, 0.025 mol), the mixturewas stirred for 1 h at -78° C., and then was allowed to warm to -10° C.The mixture was quenched with saturated ammonium chloride solution andstirred overnight. The organic layer was dried over sodium sulfate,concentrated in vacuo, and the residue was purified by HPLC to afford10.3 g of 1,1-di[1-(p-methoxyphenyl)methylimidazol-2-yl]ketone.

(b)

To a solution of potassium t-butoxide (3.56 g, 0.032 mol) in 15 ml ofTHF cooled at 0° C. was added methyltriphenyl-phosphonium bromide (1.143g; 0.03 mol) and the resulting mixture was allowed to warm to roomtemperature with stirring for 1 hour. To the above mixture was added1,1-di[1-(p-methoxyphenyl)methylimidazol-2-yl]ketone (8.5 g, 21 mmol) in30 ml of THF, followed by stirring for 2 hours at room temperature. Theabove mixture was quenched with saturated ammonium chloride solution,stirred, and filtered through a pad of SUPERCEL®. The filtrate wasconcentrated in vacuo and the residue was purified by chromatography onsilica (ethyl acetate, ethyl acetate/ether/methanol) to afford 3 g (35%)of 1,1-di[1-(p-methoxyphenyl)methylimidazol-2-yl)]ethylene (Formula III:R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR208##

(c)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(1.53 g; 5 mmol) and1,1-di[1-(p-methoxyphenyl)methyl-imidazol-2-yl)]ethylene (3 g; 7.5 mmol)in 25 ml of acetonitrile was refluxed for 54 h under argon. The reactionsolvent was replaced with nitromethane and the mixture was refluxed for4 days. The mixture was concentrated in vacuo, the residue was purifiedby silica gel column chromatography (methylene chloride/methanol, 20:1)to afford 2.1 g (59%) of6,11-ethano-12,12-di[1-(p-methoxy-phenyl)methylimidazol-2-yl]-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═##STR209##

(d)

A solution of 2.1 g (3 mmol) of6,11-ethano-12,12-di[1-(p-methoxyphenyl)methylimidazol-2-yl]-6,11-dihydro-benzo[b]quinoliziniumhexafluorophosphate in 15 ml of trifluoroacetic acid was refluxed undernitrogen for 24 h. The mixture was concentrated in vacuo, the residuewas dissolved in methanol/water and filtered, and the filtrate wasconcentrated in vacuo to afford 2 g of6,11-ethano-12,12-di-(imidazol-2-yl)-6,11-dihydrobenzo[b]quinoliziniumtrifluoroacetate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR210##as a solid.

(e)

6,11-Ethano-12,12-di-(imidazol-2-yl)-6,11-dihydrobenzo[b]quinoliniumtrifluoroacetate (2 g) in acetonitrile/water (1:1) was converted to thecorresponding chloride by passing the salt through DOWEX® 1×2-200-Cl⁻(water/acetonitrile, 7:3) to afford 0.9 g of6,11-ethano-12,12-di(imidazol-2-yl)-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═ ##STR211## as asolid.

EXAMPLE 174

A mixture of 0.5 g (2.9 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate and CS₂ CO₃ (1.04 g, 3.2 mmol) in 20 ml of acetonitrile wasstirred at room temperature for 10 minutes. To the above mixture wasadded trimethylacetyl chloride (0.52 g, 4.4 mmol) and the mixture wasstirred at room temperature. The reaction mixture was concentrated invacuo, the residue was triturated in ether and water respectively, andfiltered. The above product was dissolved in acetonitrile and passedthrough DOWEX® 1×2-200-Cl⁻ column to afford 0.27 g of6,11-ethano-12,12-di(3-furyl)-10-trimethylacetyloxy-6,11dihydrobenzo-[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═OC(O)C(CH₃)₃ ; X⁻ ═Cl⁻) as a solid, m.p. 128°-131° C.

EXAMPLE 175 (a)

A reaction mixture containing 10-hydroxy-benzo[b]quinoliziniumperchlorate (1.42 g; 5 mmol) and1,1-di[3-(2-p-methoxy-benzyl)-pyrazolyl-3yl]ethylene (2.6 g; 6.5 mmol)in 50 ml of nitromethane was refluxed for 16 h under nitrogen. Thereaction mixture was concentrated in vacuo, the residue was trituratedin ether and filtered, and the solid was purified by silica gel columnchromatography (methylene chloride/ether 9:1) to afford 3.4 g of6,11-ethano-12.12-di[3-(2-p-methoxybenzyl)-pyrazolyl-3-yl]-6,11-dihydrobenzo[b]-quinoliniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR212## R⁷═10--OH; X⁻ ═ClO₄ ⁻), as a solid.

(b)

A solution of 3.4 g (4.9 mmol) of6,11-ethano-12,12-di[3-(2-p-methoxybenzyl)-pyrazolyl-3-yl]-6,11-dihydro-benzo[b]quinoliziniumperchlorate in 50 ml of trifluoroacetic acid was refluxed under nitrogenfor 24 h. The mixture was concentrated in vacuo, the residue trituratedin methanol-water (1:1 ), and filtered. The filtrate was concentrated invacuo and the solid product was converted to the corresponding chlorideby passing the salt through DOWEX® 1×2-200-Cl⁻ (water/acetonitrile,1:1)) to afford 2.8 g of a crude product. The crude product was purifiedby repeating the above process of trifluoroacetic acid treatmentfollowed by ion exchange chromatography to afford 2.0 g of6,11-ethano-12,12-di-[pyrazolyl-3-yl]6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR213## R⁷ ═10--OH;X⁻ ═Cl⁻) as a solid, m.p. 308°-310° C.

EXAMPLE 176 (a)

A reaction mixture of 3.02 g (20 mmol) of 2-(1,3-dioxolan-2-yl)pyridineand 4.58 g (20 mmol) of methyl a-bromophenyl-acetate was stirred at roomtemperature for 4 days. The mixture was triturated in ether/ethylacetate and filtered to afford 5.7 g of1-[(a-phenyl)methoxycarbonylmethyl]-2-(1,3-dioxolan-2-yl)pyridiniumiumbromide, (Formula VI: R¹ ═H; R² ═CO₂ CH₃ ; R⁷ ═H; Z⁻ ═Br⁻).

(b)

A mixture of1-[(a-phenyl)methoxycarbonylmethyl]-2-(1,3-dioxalan-2-yl)pyridiniumiumbromide (5.6 g, 14.74 mmol) and 60 g of PPA was heated at 120° C. undernitrogen for 8 hours. The excess PPA was decomposed by the addition ofice, the reaction mixture was stirred and filtered through a SUPERCEL®pad, and to the filtrate was added sodium perchlorate solution. Theresulting solid was filtered, washed with water, and dried to afford 3 g(68%) of 6-methoxycarbonyl-benzo[b]quinolizinium perchlorate (FormulaII: R¹ ═R⁷ ═H; R² ═CO₂ CH₃ ; X⁻ ═ClO₄ ⁻) as a solid.

(c)

A reaction mixture containing 6-methoxycarbonylbenzo[b]quinoliniziumperchlorate (2.8 g; 8.3 mmol) and 1,1-di(3-furyl)ethylene (1.73 g) in 75ml of acetonitrile was allowed to reflux under argon with stirring for24 hours. The reaction mixture was concentrated in vacuo, the residuewas recrystallized from acetone/methylene chloride to afford 2.5 g of6,11-ethano-12,12-di(3-furyl)-6-methoxycarbonyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CO₂ CH₃ ; R⁵ ═R⁶═3-furyl; X⁻ ═CIO₄ ⁻) as a solid.

(d)

6,11-Ethano-12,12-di(3-furyl)-6-methoxycarbonyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.21 g, 2.8 mmol) was converted to the correspondingchloride salt by passing the above salt through DOWEX® 1×2-200-Cl⁻ afterplacing the salt in acetonitrile. The product was recrystallized frommethylene chloride/acetone to afford 0.55 g (13.1%) of6,11-ethano-12,12-di(3-furyl)-6-methoxycarbonyl-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R³ ═R⁴ ═R⁷ ═H; R² ═CO₂ CH₃ ; R⁵ ═R⁶ ═3-furyl;X⁻ ═Cl⁻) as a solid, m.p. 210°-212° C.

EXAMPLE 177

A mixture of6,11-ethano-12,12-di(m-methoxyphenyl)-6,11-dihydrobenzo[b]quinoliziniumperchlorate (3.5 g) in 50 ml of 48% HBr/acetic acid (1:1) was refluxedovernight. The reaction mixture was concentrated in vacuo, the residuewas triturated with 100 ml of water and filtered. The solid residue wasdissolved in methanol and treated with 0.9 g of sodium perchlorate in100 ml of water. The organic solvent was removed in vacuo and the solidproduct was filtered and dried to afford 2.7 g (88%) of6,11-ethano-12,12-di(m-hydroxyphenyl)-6,11 -dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-hydroxyphenyl;X⁻ ═ClO₄ ⁻) as a solid, m.p. 150°-160° C.

EXAMPLE 178 (a)

To a suspension of NaH (0.98 g, 0.039 mol) in THF was added ethanol (1.8g, 0.039 mol) followed by 1,1-dimethylsuccinic anhydride (5 g, 0.037mol), and the mixture was stirred at room temperature for 2 hour andthen poured into 1N HCl solution. The mixture was extracted with ethylacetate, the organic layer was dried and concentrated in vacuo. Theresidue was crystallized from hexane to afford 1.8 g of3-ethoxycarbonyl-3,3-dimethylpronionic acid as a solid.

(b)

A mixture of 3-ethoxycarbonyl-3,3-dimethylpropionic acid (1 g) and 3 mlof thionyl chloride was stirred at room temperature for 20 hours. Theexcess thionyl chloride was removed in vacuo to afford 1.1 g of3-ethoxycarbonyl-3,3-dimethylpropionyl chloride.

(c)

To a solution of 1.3 g (2.8 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 50 ml of acetonitrile was added CS₂ CO₃ (1.86 g, 5.7mmol) and the reaction mixture was stirred for 10 minutes. To the abovemixture was added 1.1 g (5.7 mmol) of3-ethoxycarbonyl-3,3-dimethylpropionyl chloride in 3 ml of methylenechloride and the mixture was stirred at room temperature under nitrogenfor 20 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was crystallized from methylenechloride/ethyl acete/methanol (7:2:1) and purified by triturating inethyl acetate to afford 0.85 g (50%) of6,11-ethano-12,12-di(3-furyl)-10-(OC(O)C(CH₃)₂ CH₂ CO₂Et)-6,11-dihydrobenzo[b]quinolizinium perchlorate (Formula I: R¹ ═R² ═R³═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10--OC(O)C(CH₃)₂ CH₂ CO₂ Et; X⁻ ═ClO₄ ⁻).

(d)

The above 6,11-ethano-12,12-di(3-furyl)-10-(OC(O)C(CH₃)₂ CH₂ CO₂Et)-6,11-dihydrobenzo[b]quinolizinium perchlorate (0.8 g) was convertedto the corresponding chloride salt by dissolving in acetonitrile andpassing through DOWEX® 1×2-200-Cl⁻ column to afford 0.57 g of6,11-ethano-12,12-di(3-furyl)-10-(OC(O)C(CH₃)₂ CH₂CO2Et)-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹ ═R² ═R³═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10--OC(O)C(CH₃)₂ CH₂ CO₂ Et; X⁻ ═Cl⁻).

EXAMPLE 179 (a)

A reaction mixture containing 10-methoxy-benzo[b]quinoliziniumperchlorate (0.774 g; 2.5 mmol)and1,1-di[3-(1-p-methoxybenzyl)-pyrazolyl-3-yl]ethylene (1.2 g; 3 mmol) in25 ml of nitromethane was refluxed for 14 h under nitrogen. The reactionmixture was concentrated in vacuo, the residue was triturated in ether,and the solid product was recrystallized from ether/methanol/methylenechloride to afford 1.7 g (95%) of6,11-ethano-12,12-di[(1-p-methoxybenzyl)-pyrazolyl-3yl]-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR214## R⁷═10--OCH₃ ; X⁻ ═ClO₄ ⁻), as a solid.

(b)

A mixture of 1.65 g (2.32 mmol) of6,11-ethano-12,12-di[(1-p-methoxybenzyl)-pyrazolyl-3-yl-10-methoxy-6,11-dihydrobenzo[b]quinolizinium perchlorate in 20 ml oftrifluoroacetic acid was refluxed with stirring under argon for 48 h.The mixture was concentrated in vacuo, the residue dissolved inmethanol/water (50%), filtered, and the filtrate was concentrated. Theresidual perchlorate salt was converted to the corresponding chloridesalt by dissolving in acetonitrile and passing through DOWEX®1×2-200-Cl⁻column and crystallized from isopropanol/water to afford 0.8 g (85%) of6,11-ethano-12,12-di(pyrazolyl-3-yl]-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR215## R² ═10--OCH₃; X⁻ ═Cl⁻), as a solid.

EXAMPLE 180 (a)

A mixture of 1-isoquinolinecarboxylic acid (25 g.0.14 mol), 25 g ofAMBERLYST®-15 (H+), and 300 ml of methanol was refluxed for 3 days. Thereaction mixture was cooled, filtered, and the filtrate was concentratedin vacuo to afford 13.6 g (50%) of 1-isoquinolinecarboxylic acid methylester.

(b)

1-Isoquinolinecarboxaldehyde (7.3 g, 64%) was prepared from1-isoquinolinecarboxylic acid methyl ester (13.6 g, 0.073 mol) and 1MLAH (36.6 ml in THF) in 300 ml of dry THF (J. Org. Chem., vol 28, p1898, 1963) to afford 7.3 g (64%) of 1-isoquinolinecarboxaldehyde.

(c)

A mixture of 1-isoquinolinecarboxaldehyde (7.2 g, 46 mmol), 5.7 g (92mmol) of ethylene glycol, 200 ml of toluene and 2.3 g (12 mmol) ofp-toluenesulfonic acid under argon in a 3 neck-flask equipped with aDean-Stark Trap was refluxed for 6 h separating the water. The mixturewas cooled to room temperature, and poured into an ice-cold 10% sodiumcarbonate solution. The aqueous layer was extracted with ether, thecombined organic layer was washed with brine, dried over sodium sulfate,and concentrated in vacuo to afford 9.3 g of1-(1,3-dioxolan-2-yl)isoquinoline.

(d)

A reaction mixture of 9.5 g (46 mmol) of1-(1,3-dioxolan-2-yl)isoquinoline and 7.91 g (46 mmol) of benzyl bromidewas stirred for 72 hours. The mixture was cooled to room temperature,triturated with ethyl acetate, filtered, and the solid was washed withether and dried to afford 15.2 g (88%) of1-(1,3-dioxolan-2-yl)-2-benzylisoquinolium bromide (Formula VI: R¹ is abenzene ring fused at the 3,4-positions; R² ═R⁷ ═H; Z⁻ ═Br⁻).

(e)

A mixture of 1-(1,3-dioxolan-2-yl)-2-benzylisoquinolium bromide (15.1 g,21 mmol) and 200 ml of 48% HBr was refluxed with stirring for 24 hours.The mixture was cooled to room temperature, concentrated in vacuo, andthe resulting brown residue was redissolved in water. The aqueoussolution was filtered and the the filtrate was treated with KPF₆solution. The precipitated product was filtered, washed with water,dried in vacuo, and recrystallized from acetone to afford 6.9 g (45%) ofdibenzo[a,g]quinolizinium hexafluorophosphate (Formula II: R¹ ═a benzenering fused to the 1,2-position; R³ ═R⁷ ═H; X⁻ ═PF₆ ⁻).

(f)

A reaction mixture containing dibenzo[a,g]quinoliziniumhexafluorophosphate (2.5 g; 6.6 mmol) and 1,1-di(3-furyl)ethylene (1.28g; 8 mmol) in 70 ml of acetonitrile was allowed to reflux under argonwith stirring for 24 h. The reaction mixture was concentrated in vacuo,the residue was recrystallized from methylene chloride/ether to afford3.3 g of 14,14-di(3-furyl)-8,13-ethano-8,13-dihydrodibenzo[a,g]quinolizinium hexafluorophosphate (Formula I: R¹ ═a benzene ring fusedat the 1,2-position; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻ ═PF₆ ⁻).

(g)

14,14-Di(3-furyl)-8,13-ethano-8,13-dihydrodibenzo[a,g]quinoliziniumhexafluorophosphate (3.2 g, 6.34 mmol) in acetonitrile was converted tothe corresponding chloride by passing the salt through DOWEX® 1×2-200-Cl⁻ (water/acetonitrile, 7:3) to afford 2.4 g (94%) of14,14-di(3-furyl)-8,13-ethano-8,13-dihydrodibenzo[a,g]quinoliziniumchloride (Formula I: R¹ ═a benzene ring fused at the 1,2-position; R²═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻ ═Cl⁻) as a solid, m.p. 235°-237° C.

EXAMPLE 181 (a)

To a solution of 1,1-di(3-furyl)ketone (36.7 g, 0.226 mol) in 400 ml ofTHF at 0° C. was added ethylmagnesium bromide (3M in ether, 98.1 ml,0.294 mol) and the resulting mixture was allowed to warm to roomtemperature in 30 minutes. The mixture was cooled to 0° C., quenchedwith 300 ml of ammonium chloride solution, and the resulting mixture wasextracted with ethyl acetate (3×250ml). The organic layer was dried oversodium sulfate and concentrated in vacuo to afford 43 g of1,1-di(3-furyl)propanol as an oil.

(b)

A mixture of 1,1-di(3-furyl)propanol (43 g) and 1 g of p-toluenesulfonicacid in 300 ml of toluene was allowed to react at room temperature andthe resulting mixture was concentrated in vacuo. The residual red oilwas purified by silica gel column chromatography (methylene chloride)and kugelrohr distillation (50°-80° C. at 0.25 mmHg) to afford 4 g of1,1-di(3-furyl)-1-propene (Formula III: R³ ═CH₃ ; R⁴ ═H; R⁵ ═R⁶═3-furyl) as an oil, b.p. 50°-80° C. (0.25 mm).

(c) & (d)

A reaction mixture containing benzo[b]quinolizinium hexafluorophosphate(5.8 g; 19.1 mmol) and 1,1-di(3-furyl)-1-propene (4 g; 22.9 mmol) in 300ml of nitromethane was refluxed for 12 h under nitrogen. The reactionmixture was decanted, the liquid was concentrated in vacuo, the residuewas triturated in ether (200 ml), and filtered. The solid product waspurified by silica gel chromatography (1:1 ethylacetate/PAW) andpreparative HPLC (C-18, Waters 4000, 55% MEOH, 45% H₂ O 10 mM KPF₆) toafford two isomers:

Isomer 1;6,11-ethano-12,12-di(3-furyl)-13-methyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Example 181 (c) Formula I: R¹ ═R² ═R⁴ ═R⁷ ═H; R³═CH₃ ; R⁵ ═R⁶ ═3-furyl; X⁻ ═PF₆ ⁻); 42 mg.

Isomer 2;6,11-ethano-12,12-di(3-furyl)-13-methyl-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (Example 181 (d) Formula I: R¹ ═R² ═R³ ═R⁷ ═H; R⁴═CH₃ ; R⁵ ═R⁶ ═3-furyl; X⁻ ═PF₆ ⁻); 128 mg.

EXAMPLE 182 (a)

To a solution of 2,6-di(tetrahydro-2H-2-pyranyloxymethyl)-phenyl bromide(15.5 g, 39 mmol) in ether at -30° C. was added n-BuLi (2.5M, 16.4 ml,41 mmol) and the mixture was allowed to warm to room temperature andstirred for 1.5 hours. The mixture was cooled to 0° C., and TMEDA (4.56g, 37 mmol) was added, and the resulting mixture was cooled to -50° C.After stirring for 20 minutes, 2-pyridylcarboxaldehyde (6.31 g, 58 mmol)was added. The above mixture was warmed to room temperature over aperiod of 2 hours, quenched with saturated sodium bicarbonate, anddiluted with ethyl acetate with stirring. The organic layer was washedwith brine and concentrated in vacuo to afford 11.7 g (73%) of1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanolas an oil.

(b)

A solution of 1 g (2.42 mmol) of1-(2-pyridyl)-1-[2,6-di(tetrahydro-2H-2-pyranyloxymethyl)phenyl]-methanolin 14 ml of acetic acid/THF/water (4:2:1) was heated at 100° C. undernitrogen for 6 hours. The mixture was concentrated in vacuo, the residuewas dissolved in ethyl acetate and concentrated in vacuo. The residualsolid was triturated with ether to afford 0.26 g of1-(2-pyridyl)-1-[2,6-di(hydroxymethyl)-phenyl]methanol (Formula X: R¹═R² ═H; R⁷ ═6-hydroxymethyl) as a solid.

(c)

A mixture of 0.6 g (2.5 mmol) of1-(2-pyridyl)-1-[2,6-di(hydroxymethyl)-phenyl]methanol and 10 ml ofPOCl₃ was refluxed with stirring for 4 hours. The mixture was cooled,poured onto ice, stirred and treated with a 20% sodium perchloratesolution. The resulting mixture was filtered, the resulting solid waswashed with water, and dried to afford 0.58 g of10-chloromethylrbenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R²═H; R⁷ ═10--CH₂ Cl; X⁻ ═ClO₄ ⁻).

(d)

A reaction mixture containing 10-chloromethyl-benzo[b]quinoliziniumperchlorate (0.58 g; 1.8 mmol) and 1,1-di(3-furyl)-ethylene (1 g, 6.1mmol) in 50 ml of acetonitrile was refluxed under nitrogen for 10 hours.The reaction mixture was concentrated in vacuo and the residue wascrystallized from methanol/isopropanol (3:1) to afford 0.75 g of6,11-ethano-12,12-di(3-furyl)-10-chloromethyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10--CH₂Cl; X⁻ ═ClO₄ ⁻) as a solid.

(e)

To a solution of6,11-ethano-12,12-di(3-furyl)-10-chloromethyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (0.5 g) in 65 ml of acetone was added NaI (0.3 g, 2 equiv),and the mixture was heated at 50°-60° C. for 5 hours. The mixture wasfiltered and the filtrate was concentrated in vacuo to afford 0.8 g ofthe iodide. To a solution of the iodide in 150 ml of acetone/water (1:1) was added 0.5 g of sodium carbonate and the mixture was refluxed undernitrogen for 16 hours. The solvent was removed in vacuo and the residuewas treated with a 10% sodium perchlorate solution. The resulting solidswere collected by filtration and crystallized from acetonitrile toafford 0.18 g of6,11-ethano-12,12-di(3-furyl)-10-hydroxymethyl-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═CH₂ OH;X⁻ ═ClO₄ ⁻) as a solid, m.p. 224°-226° C.

EXAMPLE 183 (a)

A mixture of 9 g (35 mmol) of1-(2-pyridyl)-1-[(2-hydroxymethyl)-5,6-methylenedioxyphenyl]methanol and30 ml of POCl₃ was refluxed with stirring for 6 hours, the mixture wascooled to room temperature, and poured into ice/water. The mixture wastreated with KPF₆ solution, the resulting solid was filtered, and washedwith water, and dried to afford 6.3 g of9,10-methylenedioxy-benzo[b]quinolizinium hexafluorophosphate (FormulaII: R¹ ═R² ═H; R⁷ ═9,10--OCH₂ O--; X⁻ ═PF₆ ⁻).

(b)

A reaction mixture containing 9,10-methylenedioxybenzo[b]quinoliziniumhexafluorophosphate (1.85 g; 5 mmol) and 1,1-di(3-furyl)-ethylene (1 g,6.25 mmol) in 25 ml of acetonitrile was allowed to reflux under nitrogenwith stirring for 18 hours. The reaction mixture was concentrated invacuo and the residue was purified by silica gel column chromatography(methylene chloride/methanol, 9:1) to afford 1.5 g (56%) of6,11-ethano-12,12-di(3-furyl)-9,10-methylenedioxy-6,11-dihydrobenzo[b]quinoliziniumhexafluoro-phosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═9,10--OCH₂ O--; X⁻ ═PF₆ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(3-furyl)-9,10-methylenedioxy-6,11-dihydrobenzo[b]quinoliziniumhexafluorophosphate (1.5 g) was converted to the corresponding chloridesalt by passing the above salt through DOWEX® 1×2-200-Cl⁻ after placingthe salt in acetonitrile. The chloride residue obtained wasrecrystal-lized from water and dried in vacuo to afford 1.0 g (47%) of6,11-ethano-12,12-di(3-furyl)-9,10-methylenedioxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9,10--OCH₂O--; X⁻ ═PF₆ ⁻) as a solid, m.p. 198°-200° C.

EXAMPLE 184 (a)

To a cooled (-78° C.) solution of 1-(p-toluenesulfonyl)-pyrazole (18.2g, 0.082 mol) in 400 ml of THF was added at -78° C. in portions 53.1 ml(0.0903 mol) of t-butyllithium (2.5M) and the mixture was stirred at-78° C. for 10 minutes. To the above mixture was added at -78° C.3-(N-methyl-N-methoxycarbamoyl)furan (14 g, 0.0903 mol) and the mixturewas stirred for 1 h at -78° C., and then was allowed to warm to roomtemperature. The mixture was poured into 1N HCl solution, extracted withethyl acetate (3×150ml), the organic layer was dried over sodiumsulfate, concentrated in vacuo, and the residue was purified by silicagel column chromatography (ether:hexane, 2:1). The residue was taken upin ether, filtered and the filtrate was concentrated in vacuo to afford6.9 g of 1-(3-furyl)-1-[1-(p-toluenesulfonyl)pyrazol-5-yl]ketone.

(b)

To a solution of methyltriphenyl-phosphonium bromide (7.71 g; 21.5 mmol)in 100 ml of ether cooled to -30° C. was added n-BuLi (8.6 ml, 2.5Mhexane, 21.5 mmol). The resulting mixture was allowed to warm to roomtemperature with stirring for 1 hour. To the above mixture was added1-(3-furyl)-1-[1-(p-toluenesulfonyl)pyrazol-5-yl]ketone (6.5 g, 20 mmol)in 25 ml of THF, then the mixture was refluxed for 1 hour. The abovemixture was cooled, filtered, and the filtrate was concentrated invacuo. The residue was purified by chromatography on silica(hexane/methylene chloride, 1:1) to afford 3.51 g of1-(3-furyl)-1-[1-(p-toluenesulfonyl)pyrazol-5-yl]ethylene (Formula III:R³ ═R⁴ ═H; R⁵ ═3-furyl; R⁶ ═ ##STR216## as a yellow oil.

(c) & (d)

A reaction mixture containing benzo[b]quinolizinium bromide (2.3 g; 8.86mmol) and 1-(3-furyl)-1-[1-(p-toluenesulfonyl)-pyrazol-5-yl]ethylene(3.2 g; 10.19 mmol) in 75 ml of nitromethane was refluxed for 2 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas triturated with ether and filtered to yield a tan solid. The solidwas purified by silica gel column chromatography (10% methanol inmethylene chloride) to afford:

Isomer 16,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfonyl)pyrazol-5-yl]-6,11-dihydrobenzo[b]quinoliziniumbromide (138 mg; Example 184(c) Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═##STR217## R⁶ ═3-furyl; X⁻ ═Br⁻). m.p. 158°-163° C.

Isomer 26,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfonyl)pyrazol-5-yl]-6,11-dihydrobenzo[b]quinoliziniumbromide (104 mg; Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═3-furyl; R⁶ ═##STR218## X⁻ ═Br⁻). m.p. 205°-211° C.

EXAMPLE 185 (a)

To a solution of6,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfonyl)pyrazol-5-yl]-6,11-dihydrobenzo[b]quinoliziniumbromide (2.03 g, 35 mmol; Example 184(c)) in 20 ml of ethanol was addedNaOMe (0.094 g, 3.5 mmol) and the mixture was stirred for 4 hours. Themixture was concentrated in vacuo, and the residue was purified bysilica gel chromatography (10% methanol in methylene chloride). Theproduct (bromide) was treated with a sodium perchlorate solution,filtered and the solid was recrystallized from isopropanol to afford1.44 g of6,11-ethano-12-(3-furyl)-12-(5-pyrazolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═5-pyrazolyl; R⁶═3-furyl; X⁻ ═ClO₄ ⁻), m.p. 122°-130° C.

(b)

To a solution of6,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfonyl)pyrazol-5-yl]-6,11-dihydrobenzo[b]quinoliziniumbromide (0.6 g, 10 mmol; Example 184(d)) in 25 ml of ethanol was addedNaOMe (0.094 g, 3.5 mmol) and the mixture was stirred for 4 hours. Themixture was concentrated in vacuo, the residue was dissolved in 5 ml ofmethanol and 20 ml of water and was treated with a sodium perchloratesolution, and filtered. The solid product was recrystallized fromisopropanol and methylene chloride to afford 98.3 mg of6,11-ethano-12-(3-furyl)-12-(5-pyrazolyl]-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═3-furyl; R⁶═pyrazolyl; X⁻ ═ClO₄ ⁻), m.p. 142° C.

EXAMPLE 186 (a)

To a solution of 3-amino-4-methylbenzoic acid methyl ester (25 g, 0.15mol) in 1 L of acetic acid cooled to 0° C. was added a solution of NaNO₂(12.5 g, 0.182 mol) in 50 ml of water and the mixture was warmed to roomtemperature with stirring over 4 hours. The solution was concentrated invacuo, the residue was triturated with water, the solid was filtered andwashed with water and hexane to afford 19 g (71.6%) of methylindazole-6carboxylate.

(b)

To a solution of methyl indazole-6-carboxylate (19 g, 0.107 mol) in 100ml of DMF was added NaH (3.3 g, 0.135 mol) and the mixture was stirredat room temperature for 1 hour. To the above mixture cooled to 0° C. wasadded trimethylsilyl-ethoxymethyl chloride (22.4 g, 0.135 mol), and themixture was stirred at room temperature for 3 hours. The mixture waspoured into 300 ml of water, and the resulting mixture was extractedwith ether. The organic layer was washed with water and brine, dried,and concentrated in vacuo to afford 3.7 g (52.5%) of methyl1-(trimethylsilylethoxymethyl)-indazole-6-carboxylate.

(c)

To a mixture of LAH (5.73 g, 0.15 mol) in 200 ml of ether was added asolution of methyl 1-(trimethylsilylethoxymethyl)-indazole-6-carboxylatein 200 ml of ether over a 30 minutes period and the mixture was stirredfor 1 hour. The resulting mixture was quenched with water (6 ml), 1NNaOH (15 ml) and water (6 ml), diluted with ethyl acetate with stirringand filtered. The filtrate was concentrated in vacuo, and the residuewas crystallized from hexane/ethyl acetate (2:1) to afford 18.1 g (87%)of 1-(trimethylsilylethoxymethyl)indazolyl-6-methanol.

(d)

A mixture of 1 -(trimethylsilylethoxymethyl)indazolyl-6-methanol (18.1g, 65 mmol) in 400 ml of 50% aqueous acetic acid and n-bromosuccinimide(NBS) (12.6 g, 71 mmol) was stirred at room temperature for 20 minutes.The resulting solid was filtered, washed with water and hexane, anddried to afford 16.8 g (72.1%) of1-(trimethylsilylethoxymethyl)-5-bromoindazol-yl-6-methanol.

(e)

A mixture of 1-(trimethylsilylethoxymethyl)-5-bromoindazol-yl-6-methanol(16.8 g, 47 mmol), triphenylphosphine (15 g, 56 mmol), and carbontetrabromide (18.6 g, 56 mmol) in 500 ml of methylene chloride wasstirred under nitrogen overnight. The mixture was concentrated in vacuoand the solid was crystallized from hexane/ethyl acetate 9:1) to afford5.1 g (25.8%) of1-(trimethylsilylethoxymethyl)-5-bromo-6-bromo-methyl-indazole.

(f)

A mixture of1-(trimethylsilylethoxymethyl)-5-bromo-6-bromo-methylindazole (5.1 g, 12mmol) and 1-[2-(1,3-dioxolanyl)]-pyridine (1.9 g, 12.7 mmol) was stirredat room temperature under nitrogen for 48 hours. The mixture wastriturated with ether and decanted. The residue was dissolved in warmwater, filtered, and the filtrate was treated with a KPF₆ (1.5 g)solution with stirring. The solid product was filtered and dried toafford 5.8 g (75.3%) of 1-[1-(trimethylsilylethoxy-methyl)-5-bromo]indazol-6-ylmethyl-2-(1,3-dioxolanyl)-pyridiniumhexafluoro-phosphate.

(g)

To a mixture of polyphosphoric acid (125 ml) and methanesulfonic acid(25 ml) at 100° C. was added 5.8 g (9.1 mmol) of1-[1-(trimethylsilylethoxymethyl)-5-bromo]indazol-6-yl-methyl-2-(1,3-dioxolanyl)pyridiniumhexafluorophosphate and the mixture was allowed to react at 100° C. for5 hours. The mixture was cooled to room temperature, diluted with 125 mlof warm water and 800 ml of methanol, and the resulting mixture wastreated with a 30% KPF₆ solution. The solid was filtered, dissolved in500 ml of acetonitrile and filtered. The filtrate was concentrated invacuo, the residue was filtered and washed with ether to afford 2.3 g(57%) of 7-bromo-9,10-pyrazolo-benzo[b]quinolizinium hexafluorophosphate(Formula II: R¹ ═R² ═H; R⁷ ═7--Br; ##STR219## X⁻ ═PF₆ ⁻).

(h)

A reaction mixture containing 7-bromo-9,10pyrazolobenzo[b]quinoliziniumhexafluorophosphate (2.5 g; 5.2 mmol) and 1,1-di(3-furyl)ethylene (1.26g; 7.8 mmol) in 75 ml of acetonitrile was allowed to reflux undernitrogen with stirring for 8 h. The reaction mixture was concentrated invacuo, the residue was crystallized from methanol to afford 2.3 g(73.4%) of12,12-di(3-furyl)-7-bromo-6,11-ethano-6,11-dihydro-9,10-pyrazolobenzo[b]quinoliziniumhexafluoro-phosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷═7--Br; ##STR220## X⁻ ═PF₆ ⁻).

(i)

To a solution of12,12-di(3-furyl)-7-bromo-6,11-ethano-6,11-dihydro-9,10-pyrazolobenzo[b]quinoliziniumhexafluorophosphate (2.2 g, 3.6 mmol) in methanol/acetonitrile (150 ml,5:1) was added 1 g of 5% Pd/CaCO₃ and the mixture was hydrogenated at 50psi for 3 hours. The mixture was filtered, the filtrate wasconcentrated, and the residue was purified by column chromatography(methylene chloride/ethyl acetate/methanol, 7:2:1). The above solid wasrecrystallized from isopropanol/ethyl acetate/methanol (1:4:1) to afford1.2 g (62.8%) of12,12-di(3-furyl)-6,11-ethano-6,11-dihydro-9,10-pyrazolobenzo[b]quinoliziniumhexafluorophosphate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═##STR221## C⁻ ═PF₆ ⁻).

(j)

12,12-Di(3-furyl)-6,11-ethano-6,11-dihydro-9,10-pyrazolobenzo[b]quinoliziniumhexafluorophosphate (1.2 g, 2.3 mmol) in acetonitrile/water (1:1) wasconverted to the corresponding chloride by passing the salt throughDOWEX® 1 ×2-200-Cl⁻ (water/acetonitrile, 7.3) to afford 0.61 g (64.2%)of12,12-di(3-furyl)-6,11-ethano-6,11-dihydro-9,10-pyrazolobenzo[b]quinoliziniumchloride (Formula I: R⁻ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═ ##STR222##X⁻ ═Cl⁻), as a solid.

EXAMPLE 187 (a)

To a solution of 3-hydroxy-4-chlorotoluene (25 g, 0.175 mol) in 400 mlof acetone was added 30.11 g (0.22 mol) of milled potassium carbonateand 31.22 g (0.22 mol) of methyl iodide, and the mixture was refluxedwith stirring for 16 hours. The mixture was cooled, filtered, and thefiltrate was concentrated in vacuo. The residue was dissolved in ether,washed with water, and the organic layer was dried over sodium sulfateand concentrated in vacuo to afford 25.6 g of 3-methoxy-4-chlorotolueneas a solid.

(b)

A mixture of 3-methoxy-4-chlorotoluene (25.5 g, 0.163 mol) and KMnO₄ (62g, 0.392 mol) in 1.2 L of water was refluxed with stirring for 16 hours.The mixture was filtered, the filtrate was neutralized with cone. HClsolution (to pH=2), and the resulting solid was filtered, washed withwater, and dried to afford 3-methoxy-4-chlorobenzoic acid (17.5 g,58%).

(c)

To 30.6 ml of BH₃.THF was added a solution of 3-methoxy-4-chlorobenzoicacid (35 g, 0.187 mol) in 450 ml of THF, and the mixture was refluxedwith stirring under argon for 3 hours. The mixture was quenched withTHF/water (1:1,300 ml), concentrated in vacuo, and the residue waspartitioned between methylene chloride/water. The organic layer wasdried over sodium sulfate and concentrated in vacuo to afford 29.4 g(90%) of 3-methoxy-4-chlorophenylmethanol.

(d)

To a solution of 29 g (0.168 mol) of 3-methoxy-4-chlorophenylmethanol in600 ml of ether cooled to -20° C. was added dropwise 142 ml (0.353 mol)of 2.5M n-butyllithium in hexane and the resulting mixture was stirredat room temperature for 2 hours. The reaction mixture was cooled to 0°C., 19.52 g (0.168 mol) of TMEDA was added. The above reaction mixturewas cooled to -30° C., 26.96 g (0.252 mol) of pyridine-2-carboxaldehydein 30 ml of THF was added, and the resulting reaction mixture wasallowed to warm to 0° C. and quenched with 10 ml of water. The resultingdiol was filtered, and filtrate was extracted with ethyl acetate, driedover sodium sulfate, and the solvent was removed in vacuo. The combinedresidue was triturated with ether to afford 35.3 g (75%) of2-[1-hydroxy-(2'-hydroxymethyl-5-chloro-6-methoxy)benzyl]pyridine(Formula X: R¹ ═R² ═H; R⁷ ═5--Cl, 6--OCH₃).

(e)

A mixture of 35 g (0.125 mol) of2-[1-hydroxy-(2'-hydroxymethyl-5-chloro-6-methoxy)benzyl]pyridine and150 ml of POCl₃ was refluxed with stirring for 2 h. The mixture wascooled, poured into ice, filtered, and the filtrate was treated withsodium perchlorate solution. The resulting mixture was filtered, thesolid was washed with water, dried and recrystallized from acetonitrileto afford 3 5.1 g (8 1%) of 9-chloro-10-methoxybenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═R² ═H; R⁷ ═9--Cl, 10--OCH₃ ; X⁻ ═ClO₄ ⁻) asa solid, m.p. 234°-237° C.

(f)

A reaction mixture containing 9-chloro- 10-methoxybenzo[b]quinoliziniumperchlorate (2 g; 5.81 mmol) and 1,1-di(3-furyl)ethylene (1.11 g, 7mmol) in 50 ml of acetonitrile was allowed to reflux under nitrogen withstirring for 6 hours. The reaction mixture was concentrated in vacuo andthe residue was crystallized from methylene chloride/ethylacetate/methanol (7:2:1). The solid product was purified by silica gelchromatography (9:1 methylene chloride/methanol) to afford 3.1 g of6,11-ethano-12,12-di(3-furyl)-9-chloro-10-methoxy-6,11-dihydrobenz[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9--Cl,10--OCH₃ ; X⁻ ═ClO₄ ⁻)) as a solid.

(g)

6,11-Ethano-12,12-di(3-furyl)-9-chloro-10-methoxy-6,11-dihydrobenzo-[b]quinoliziniumperchlorate (3 g, 5.95 mmol) was converted to the corresponding chloridesalt by passing the above salt through DOWEX® 1×20-200-Cl⁻ after placingthe salt in acetonitrile. The chloride residue obtained was dried invacuo and recrystallized from methylene chloride/ether to afford 1.83 g(71%) of6,11-ethano-12,12-di(3-furyl)-9-chloro-10-methoxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ --9--Cl;10--OCH₃ ; X⁻ ═Cl⁻)

EXAMPLE 188 (a)

A reaction mixture containing 9-chloro-10-methoxybenzo[b]quinoliziniumperchlorate (5 g; 14.83 mmol) and 48% HBr (50 ml) was refluxed withstirring for 18 hours. The mixture was concentrated in vacuo, theresidue was redissolved in water, filtered, and the filtrate was treatedwith a sodium perchlorate solution with stirring for 40 minutes. Thesolid was filtered and recrystallized from acetone/ether (1:1) to afford3.8 g (79%) of 9-chloro-10-hydroxy-benzo[b]quinolizinium perchlorate(Formula II: R¹ ═R² ═H; R⁷ ═9--Cl; 10--OH; X⁻ ═CIO₄ ⁻), m.p. 203°-205°C.

(b)

A reaction mixture containing 8-chloro-9-hydroxybenzo[b]quinoliziniumperchlorate (3.3 g; 10 mmol) and 1,1-di(3-furyl)ethylene (1.76 g, 11mmol) in 50 ml of acetonitrile was allowed to reflux under nitrogen withstirring for 6 hours. The reaction mixture was concentrated in vacuo andthe residue was crystallized from methylene chloride/ethylacetate/methanol (7:2:1). The solid product was purified by silica gelchromatography (9:1 methylene chloride/methanol) to afford 3.3 g of6,11-ethano-12,12-di(3-furyl)-9-chloro-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9--Cl;10--OH; X⁻ ═ClO₄ ⁻) as a solid.

(c)

6,11-Ethano-12,12-di(3-furyl)-9-chloro-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (3.1 g) was converted to the corresponding chloride salt bypassing the above salt through DOWEX® 1×20-200-Cl⁻ after placing thesalt in acetonitrile. The chloride residue obtained was dried in vacuoand recrystallized from acetonitrile to afford 1.0 g (71%) of6,11-ethano-12,12-di(3-furyl)-9-chloro-10-hydroxy-6,11-dihydrobenzo]b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9--Cl;10--OH; X⁻ ═Cl⁻) as a solid, m.p. 256°-258° C.

EXAMPLE 189 (a)

A reaction mixture containing 8-chloro-benzo[b]quinolizinium bromide(0.5 g; 1.7 mmol)and 1,1-di[(1-p-methoxybenzyl)-pyrazol-5-yl]-ethylene(0.748 g; 1.87 mmol) in 10 ml of nitromethane was refluxed for 2 h undernitrogen. The reaction mixture was concentrated in vacuo, the residuewas purified by flash chromatography on silica (10% methanol inmethylene chloride) and treated with 10 ml of saturated sodiumperchlorate solution. The resulting solid was recrystallized fromisopropanol to afford 0.68 g (56.6%) of6,11-ethano-12,12-di[(1-p-methoxy-benzyl)-pyrazol-5-yl]-9-chloro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR223## R⁷═9--Cl; X⁻ ═ClO₄ ⁻), as a solid.

(b)

A solution of 680 mg (0.95 mmol) of6,11-ethano-12,12-di[(1-p-methoxy-benzyl)-pyrazol-5-yl]-9-chloro-6,11-dihydrobenzo-[b]quinoliziniumperchlorate in 10 ml of trifluoroacetic acid was refluxed under nitrogenfor 12 h. The mixture was concentrated in vacuo, the residue wasdissolved in 50% methanol in water, and filtered. The aqueous layer wasconcentrated in vacuo to remove methanol and the residue was treatedwith saturated sodium perchlorate in water. The resulting solid productwas filtered and triturated in isopropanol/methylene chloride to afford305 mg (67.7%) of6,11-ethano-12,12-di-(pyrazol-5-yl)]-9-chloro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR224## R⁷═9--Cl; X⁻ ═ClO₄ ⁻), as a solid.

EXAMPLE 190 (a)

A reaction mixture containing 9-hydroxy-benzo[b]quinoliziniumperchlorate (2.4 g; 8.2 mmol) and1,1-di[3-(1-triisopropyl-silyl)pyrrolyl]ethylene (5 g; 10.6 mmol) in 100ml of acetonitrile was refluxed overnight under nitrogen. The reactionmixture was filtered, the filtrate was concentrated in vacuo, and theresidue was triturated with ether to afford 2.3 g (36%) of6,11-ethano-12,12-di[3-(1-triisopropylsilyl)-pyrrolyl]-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR225## R⁷═10--OH; X⁻ ═ClO₄ ⁻), as a yellow solid.

(b)

To a solution of 2.2 g (2.9 mmol) of6,11-ethano-12,12-di[3-(1-triisopropylsilyl)pyrrolyl]-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 50 ml of methylene chloride was added tetrabutylammoniumfluoride (2.9 ml, 2.7 mmol, 1.0M) and the mixture was stirred at roomtemperature under nitrogen overnight. The solid precipitate wasconverted to the corresponding chloride salt by passing the above saltthrough DOWEX® 1×2-200-Cl⁻ after placing the salt in methanol. Thechloride residue obtained was dried in vacuo and the solid was washedwith methylene chloride, and dried to afford 0.39 g of6,11-ethano-12,12-di(3-pyrrolyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-pyrrolyl; R⁷ ═10--OH;X⁻ ═Cl⁻), as a solid, m.p. 190°-195° C.

EXAMPLE 191 (a)

3-Isoquinolinecarboxaldehyde (7 g, 84%) was prepared by reduction of3-isoquinolinecarboxylic acid methyl ester (10 g, 52 mmol) with 1M LAH(27 ml in THF, 27 mmol) in 300 ml of dry THF at -78° C. for 30 minutes.The mixture was quenched with 7 ml of acetic acid, concentrated invacuo, and the residue was purified by silica gel column chromatography(hexane/ethyl acetate, 2:1) to afford 7 g (84%) of3-iso-quinolinecarboxaldehyde.

(b)

A mixture of 3-isoquinolinecarboxaldehyde (7 g, 44.5 mmol), 5.5 g (88mmol) of ethylene glycol, 400 ml of toluene and 1.1 g (4.4 mmol) ofp-toluenesulfonic acid was refluxed for 16 h while separating the waterformed. The mixture was cooled to room temperature and washed withsodium bicarbonate solution, water, and brine. The organic layer wasdried over sodium sulfate, and concentrated in vacuo to afford 8 g(89.9%) of 3-(1,3-dioxolan-2-yl)isoquinoline (Formula XII: R² ═R⁷ ═H).

(c)

A reaction mixture of 8 g (39.7 mmol) of3-(1,3-dioxolan-2-yl)isoquinoline and 8 g (86.4 mmol) of chloroacetonein acetone was stirred at room temperature for 20 hours. To the mixturewas added 5 g of KBr and the resulting mixture was stirred. Theresulting mixture was filtered, the residual solid was stirred in 350 mlof acetonitrile and filtered. The above filtrate was concentrated invacuo, and the residue was triturated in ethyl acetate to afford 8.6 g(64.7%) of 3-(1,3-dioxolan-2-yl)-2-(2-oxopropyl)isoquinolium bromide(Formula XIV: R² ═R⁷ ═H; Z'⁻ ═Br⁻).

(d)

A mixture of 3-(1,3-dioxolan-2-yl)-2-(2-oxopropyl)isoquinolium bromide(8.6 g, 25.5 mmol) and 75 ml of 48% HBr was refluxed with stirring for 3hours. The mixture was cooled to room temperature, diluted with waterand filtered. The residue was dissolved in hot water and treated with100 ml of 25% sodium perchlorate solution. The precipitated product wasfiltered, washed with hexane, ether, and ethyl acetate and dried invacuo to afford 6.4 g (85.3%) of 3-hydroxybenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═3--OH; R² ═R⁷ ═H; X⁻ ═ClO₄ ⁻).

(e)

A reaction mixture containing 3-hydroxy-benzo[b]quinoliziniumperchlorate (1 g; 3.4 mmol) and 1,1-di(3-furyl)ethylene (1 g; 6.2 mmol)in 50 ml of acetonitrile was allowed to reflux under nitrogen withstirring for 16 h. The reaction mixture was concentrated in vacuo, theresidue was triturated in 50 ml of methylene chloride/ether (1:2) andfiltered. The solid was retriturated in ethyl acetate, filtered, theresulting solid was washed with ether to afford 1.35 g (87%) of12,12-di(3-furyl)-3-hydroxy-6,11-ethano-6,11-dihydrobenzo[b]-quinoliziniumperchlorate (Formula I: R¹ ═3--OH; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl;X⁻ ═ClO₄ ⁻).

(f)

12,12-Di(3-furyl)-3-hydroxy-6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.35 g, 2.9 mmol) in acetonitrile was converted to thecorresponding chloride by passing the salt through DOWEX® 1×2-200-Cl⁻(water/acetonitrile, 7.3). The salt was filtered, washed with coldwater, and dried to afford 0.27 g (23.7%) of12,12-di(3-furyl)-3-hydroxy-6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═3--OH; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻═Cl⁻) as a solid.

EXAMPLE 192 (a)

A mixture of 75.0g furyl-3-carboxylic acid (0.669 mol), 53.8 ml thionylchloride (0.737 mol), and 325 ml toluene was heated to reflux whilestirring overnight. Then the volume of the mixture was reduced bydistilling 150 ml. The mixture was cooled and 500 ml methylene chloride,71.9 g 30 (0.737 mol) of N,O-dimethylhydroxylamine hydrochloride and0.15 g of 4-dimethylaminopyridine was added. The mixture was cooled to0° C. and 120 ml of pyidine was added dropwise. The mixture was allowedto warm to room temperature and stirred overnight. The solids thatformed were filtered, rinsed with 600 ml methylene chloride, thendiscarded. The filtrate was extracted twice with 600 ml portions of 2NHCL then twice with 600 ml water. The methylene chloride layer was driedover magnesium sulfate, filtered and concentrated in vacuo. Theresulting dark oil was distilled through a 15 cm glass Vigreaux column,bp 115°-1250° C. at 0.4 mm Hg. Upon cooling the distillate crystallized,affording 68.5 g (66%) of 3-(N-methyl-N-methoxycarbamoyl) furan as awhite solid, mp 39°-42° C.

(b)

A solution of n-BuLi in hexane (155 ml, 2.5M, 0.39 moles) and ether(908.5 ml) was cooled to -78° C. under nitrogen. 3-bromofuran (57.3 g,0.39 mol) in ether (113.6 ml) was added dropwise while maintaining thetemperature of the mixture below -70° C. The mixture was stirred at -78°C. for 1 hour then 56.6 g (0.365 mol) of3-(N-methyl-N-methoxycarbamoyl)furan in 167 ml of ether was addeddropwise over a period of 20 minutes. The mixture was stirred overnightand allowed to warm to room temperature. The mixture was quenched with440 ml of water, and filtered. The filtrate was extracted with methylenechloride. The organic layer was concentrated in vacuo, the residue wascrystallized from t-butylmethyl ether (175 ml) and washed with hexane toafford 41.85 g (65.3%) of 1,1-di(3-furyl)ketone as an off-white coloredsolid.

(c)

To a solution of 1,1-di(3-furyl)ketone (41.85 g) in 440 ml of THF cooledto 0° C. under nitrogen with stirring was added dropwise 129.4 ml (0.38mol) of 3M methylmagnesium bromide in ether at below 10° C. The mixturewas allowed to warm to room temperature, and stirred for 4 hours. Theabove mixture was cooled to 0° C., quenched with a saturated ammoniumchloride solution and stirred for 30 minutes. The aqueous layer wasextracted with THF (440 ml), the combined organic layer was dried overmagnesium sulfate, and concentrated in vacuo (to 440 ml). The abovelayer was treated with 0.25 g of p-toluenesulfonic acid and heated toreflux for 2 hours. The solution was washed with a saturated sodiumbicarbonate solution, dried over magnesium sulfate and distilled (15 cmVigreux column bp 60° C. at 0.2 mm Hg) to afford 34.35 g of1,1-di(3-furyl)ethylene (Formula III: R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl) as aclear oil.

(d)

To a solution of 2,6-dibromoypyridine (53.9 g, 0.2275 mol) in THF (144ml)/ether (288 ml)/hexane (144 ml) at -78° C. was added dropwise n-BuLi(100 ml, 2.5M, 0.25 mol) in hexane. The mixture was stirred for 10minutes, and then DMF (36.5 g, 0.5 mol) was added. The reaction mixturewas allowed to warm to -50° C., quenched with 270 ml of methanol, andthen ethyl acetate (1 L) and 60 ml of water were added at roomtemperature with stirring. The layers were separated and the organiclayer was extracted with 2×60 ml of water. The organic layer was washedwith brine, dried over magnesium sulfate, concentrated in vacuo, and theresidue was purified by silica gel chromatography (10% ether in hexane)to afford 6-bromo-2-pyridylcarboxaldehyde (Formula IX: R¹ ═6--Br) as anoil.

(e)

To a solution of 28.4 g (0.152 mol) of 2-bromobenzyl alcohol and 22.9 ml(0.152 mol) of TMEDA in 550 ml ether cooled to -30° C. was addeddropwise 133.6 ml (0.152 mol) of 2.5M n-butyl lithium in hexanes.Stirred for 30 minutes at -30° C., then at room temperature for 1 hour.The reaction mixture was cooled to -20° C. and 25.7 g (0.138 mol) of6-bromopyridine-2-carboxaldehyde in 550 ml of ether was added. Thereaction mixture was stirred for 1 hour. The solution was allowed towarm to room temperature while stirring overnight. The mixture wasquenched with 200 ml saturated ammonium chloride solution, and 600 ml ofethyl acetate and 200 ml of methylene chloride were added. The layerswere separated and the aqueous layer was extracted with 200 ml ethylacetate. The combined organic layers were dried over magnesium sulfate,filtered and evaporated in vacuo. The residue was purified bychromatography on silica-gel with ethyl acetate-hexane (gradient)affording 12.76 g of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-6-bromopyridine (Formula X: R¹═6--Br; R² ═R⁷ ═H) as a solid, m.p. 123°-125° C.

A mixture of 12.75 g (0.0434 mol) of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-6-bromopyridine and 75 ml ofPOCl₃ was heated at 110° C. while stirring for 4 h. The mixture wascooled, concentrated in vacuo, and the residue was dissolved in water. Asolution of excess sodium perchlorate was added and the precipitatefiltered. The solid was washed with water, and was purified by silicagel chromatography (9/1 methylene chloride/methanol) to afford 1.7 g of4-chloro-benzo[b]quinolizinium perchlorate (Formula II: R¹ ═4--Cl; R²═R⁷ ═H; ClO₄ ⁻).

(g)

A reaction mixture containing 4-chloro-benzo[b]quinolizinium perchlorate(1.13 g; 3.6 mmol) and 1,1-di(3-furyl)-ethylene (0.757 g, 4.73 mmol) in50 ml of nitromethane was heated to reflux under nitrogen while stirringfor 3 hours. The reaction mixture was concentrated in vacuo and theresidue was purified by chromatography on silica gel (2/82-propanolmethylene chloride) to afford 1.36 g (83.4%) of6,11-ethano-12,12-di(3-furyl)-4-chloro-6,11-dihydrobenzo[b]-quinoliziniumperchlorate (Formula I: R¹ ═4--Cl; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl;X⁻ ═ClO₄ ⁻) as a solid.

EXAMPLE 193

A reaction mixture containing 9-hydroxy-benzo-[b]quinoliziniumperchlorate (1.4 g; 4.8 mmol) and 1,1-di(3-furyl)-ethylene (1 g, 6.2mmol) in 25 ml of acetonitrile was allowed to reflux under argon withstirring for 3 hour. The reaction mixture was concentrated in vacuo, theresidue was triturated in methanol/water (2:1), and concentrated invacuo. The residual salt was converted to the corresponding chloride bypassing the salt through DOWEX® 1×2-200-Cl⁻ (water/acetoni-trile, 7.3).The salt was filtered, washed with cold water, and dried to afford 0.31g (15%) of12,12-di(3-furyl)-9-hydroxy-6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9--OH; X⁻═Cl⁻) as a solid, m.p. 263°-265°C.

EXAMPLE 194 (a)

Bromoacetyl bromide (20 g, 99.1 mmol) was added to a solution of1-octanol (12.9 g, 99.1 mmol) and 10 ml of pyridine in 100 ml ofmethylene chloride at 0° C. After 10 minutes, the mixture was quenchedwith 100 ml of ice/water, and the aqueous layer was extracted withmethylene chloride, and the combined organic layer was washed with 1NHCl (3×100ml) and brine. The organic layer was dried over magnesiumsulfate, concentrated in vacuo, and the product was distilled under highvacuum to afford 6 g of 1-octyl bromoacetate as an oil, b.p. 93° C.

(b)

To a mixture of lithium diisopropylamide (prepared from 4.8 g, (47.8mmol) of diisopropylamine and 19.1 ml, (2.5M, 47.8 mmol) of n-BuLi) in50 ml of THF was added isobutyric acid (2.2 ml, 23.9 mmol) at 0° C. andthe mixture was allowed to warm to 45° C. with stirring. To the mixturecooled to -78° C., was added 4.3 g (23.9 mmol) of HMPA followed by asolution of 1-octyl bromoacetate (6 g, 23.9 mmol) in 50 ml of THF underargon at -78° C. The mixture was quenched with 1N HCl, warmed to roomtemperature, and extracted with ether (3×50ml). The organic layer wasdried over magnesium sulfate, concentrated in vacuo, and purified byflash chromatography (10% methanol/ethyl acetate) to afford 0.8 g of3-(1-octyloxycarbonyl)-2,2-dimethylbutyric acid.

(c)

3-(1-Octyloxycarbonyl)-2,2-dimethylbutyric acid (0.4 g) was treated withthionyl chloride (20 ml) and the excess thionyl chloride was removed invacuo to afford 0.33 g of 3-(1-octyloxycarbonyl)-2,2-dimethylbutyricacid chloride.

(d)

To a solution of 0.36 g (0.8 mmol) of6,11-ethano-12,12-di(3-furyl)-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 20 ml of acetonitrile was added CS₂ CO₃ (0.27 g, 0.8mmol) and the reaction mixture was stirred for 10 minutes. To the abovemixture was added 0.33 g (1.2 mmol) of3-(1-octyloxycarbonyl)-2,2-dimethylbutyric acid chloride in methylenechloride and the mixture was stirred at room temperature under nitrogen.The reaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by flash chromatography (10%methanol/methylene chloride) and the resulting salt was converted to thecorresponding chloride by passing the salt through DOWEX® 1×2-200-Cl⁻(water/acetonitrile, 7/3). The salt was filtered, washed with coldwater, and dried to afford 0.26 g (51%) of12,12-di(3-furyl)-10-(OC(O)C(CH₃)₂ CH₂C(O)OOctyl)-6,11-ethano-6,11-dihydrobenzo[b]quinolinizium chloride(Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═10--OC(O)C(CH₃)₂ CH₂C(O)OOctyl; X⁻ ═Cl⁻) as a solid, m.p. 60°-65° C.

EXAMPLE 195 (a)

A reaction mixture containing 9-hydroxy-benzo[b]quinoliziniumperchlorate (1 g; 3.4 mmol) and1,1-di[(1-p-methoxybenzyl)-pyrazol-3-yl]ethylene (2 g; 5.1 mmol) in 75ml of aceto-nitrile/ethanol (8:1) was refluxed for 16 h under nitrogen.The reaction mixture was filtered, the filtrate was concentrated invacuo, the residue was triturated in methanol to afford 0.75 g (32.5%)of6,11-ethano-12,12-di[(1-p-methoxy-benzyl)pyrazol-3-yl]-9-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR226## R⁷═9--OH; X⁻ ═ClO₄ ⁻), as a solid.

(b)

A solution of 750 mg (1.1 mmol) of6,11-ethano-12,12-di[(2-p-methoxy-benzyl)-pyrazol-3-yl]-9-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 60 ml of trifluoroacetic acid was refluxed under nitrogenfor 24 h. The mixture was concentrated in vacuo, the residue dissolvedin 50 ml of methanol and the solvent was removed in vacuo. The resultingresidue was triturated in methanol/water (300 ml, 1:1), the aqueouslayer was filtered, and the filtrate was concentrated in vacuo to afford500 mg of6,11-ethano-12,12-di-(pyrazol-3-yl)-9-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR227## R⁷═9--OH; X⁻ ═ClO₄ ⁻), as a solid.

(c)

6,11-Ethano-12,12-di-(pyrazol-3-yl)]-9-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (0.5 g, 1.1 mmol) was converted to the correspondingchloride by passing the salt through DOWEX® 1×2-200-Cl⁻(water/acetonitrile, 7/3). The salt was dissolved in 50 ml of boilingmethanol/water, filtered and the filtrate was concentrated in vacuo toafford 0.15 g (34.8%) of12,12-di(pyrazol-3-yl)-9-hydroxy-6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR228## R⁷ ═9--OH;X⁻ ═Cl⁻) as a solid.

EXAMPLE 196 (a)

mixture of 3.9 g (26 mmol) of 2-(1,3-dioxolan-2-yl)pyridine and 5 g (26mmol) of 4-fluorobenzyl bromide was stirred at room temperatureovernight and the resulting mixture was triturated in ether. The whitesolid was filtered and washed with ether to afford 8.1 g (91%) of2-(1,3-dioxolan-2-yl)-1-(p-fluorobenzyl)pyridinium bromide (Formula VI:R¹ ═R² ═H; R⁷ ═4--F; Z⁻ ═Br⁻).

(b)

A mixture of 8.1 g (24 mmol) of2-(1,3-dioxolan-2-yl)-1-(p-fluorobenzyl)pyridinium bromide in 100 ml of48% HBr solution was refluxed for 18 hours. The mixture was heated invacuo to remove HBr solution. The dry residue was dissolved in water,treated with an excess sodium perchlorate solution. The solid wasfiltered, washed with water, and dried in vacuo to afford 3 g (41%) of9-fluorobenzo[b]quinolizinium perchlorate (Formula II: R¹ ═R² ═H; R⁷═9--F; X⁻ ═ClO₄ ⁻).

(c)

A reaction mixture containing 9-fluorobenzo[b]quinolizinium perchlorate(0.6 g; 2 mmol) and 1,1-di(3-furyl)-ethylene (0.32 g, 6.2 mmol) in 20 mlof acetonitrile was allowed to reflux under argon with stirring for 3hour. The reaction mixture was concentrated in vacuo, the residue wastriturated in ether, redissolved in acetonitrile, treated with activatedcharcoal and filtered. The filtrate was concentrated in vacuo and theresidue was crystallized from methanol to afford 0.67 g of12,12-di(3-furyl)-9-fluoro-6,11-ethano-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furyl; R⁷ ═9--F; X⁻═CIO₄ ⁻) as a solid, m.p. 256°-258° C.

EXAMPLE 197 (a)

To a mixture of DABCO™ (5.72 g, 51 mmol) in 200 ml of ether at -20° C.was added dropwise 2.5M n-BuLi (51 mmol) and the mixture was stirred at-20° C. for 1 hour. The above mixture was cooled to -78° C., a solutionof 3-fluoropyridine (5 g, 51 mmol) in ether (25 ml) was added at -78°C., and the mixture was stirred at -60° C. for 1 hour. The abovereaction mixture was cooled to -78° C., DMF (4.2 g, 56 mmol) was addedand the mixture was stirred at this temperature for 2 hours. Thereaction mixture was allowed to warm to -10° C., quenched with 50 ml ofwater and saturated ammonium chloride solution. The aqueous layer wasextracted with ethyl acetate (3×100ml) and the combined organic layerwas dried over magnesium sulfate, concentrated in vacuo, and the residuewas purified by silica gel chromatography (1:1 ether/hexane) to afford1.5 g (23.5%) 3-fluoro-2-pyridylcarboxaldehyde (Formula IX: R¹ ═3--F).

(b)

To a solution of 2 g (10.6 mmol) of 2-bromobenzyl alcohol and TMEDA(1.24 g, 10.6 mmol) in ether (100 ml) cooled to -30° C. was added inportions 9 ml (22 mmol) of 2.5M n-butyllithium in hexane with stirringfor 30 minutes and the resulting mixture was stirred at room temperaturefor 1 hour. The reaction mixture was cooled to -20° C., 1.3 g (10.4mmol) of 3-fluoropyridine-2-carboxaldehyde in 50 ml of ether withstirring for 1 hour. 30 The resulting reaction mixture was allowed towarm to room temperature and stirred overnight and quenched with water.The resulting diol was filtered, and filtrate was extracted with ethylacetate, the organic layer was washed with brine, dried over magnesiumsulfate, and the solvent was removed in vacuo. The combined residue waspurified by silica gel chromatography (ethyl acetate) to afford 0.5 g of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-fluoropyridine (Formula X: R¹═3--F; R² ═R⁷ ═H) as a solid.

(c)

A mixture of 0.5 g (2.1 mmol) of2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-fluoropyridine and 25 ml ofPOCl₃ was heated at 110° C. with stirring for 1 h. The mixture wascooled, poured into ice/water with stirring, and sodium perchlorate (10g) solution was added. The resulting mixture was filtered, the solid waswashed with water and ether to afford 0.4 g (64%) of !-fluoro-benzo[b]quinolizinilium perchlorate (Formula II: R¹ ═1--F; R²═R⁷ ═H; X⁻ ═ClO₄ ⁻).

(d)

A reaction mixture containing 1-fluoro-benzo[b]quinolizinium perchlorate(0.35 g; 1.2 mmol) and 1,1-di(3-furyl)ethylene (0.32 g, 2 mmol) in 25 mlof acetonitrile was allowed to reflux under nitrogen with stirring for18 hours. The reaction mixture was concentrated in vacuo and the residuewas triturated in methanol, filtered, and washed with ethyl acetate andether to afford 0.4 g (72.7%) of6,11-ethano-12,12-di(3-furyl)-1-fluoro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═1--F; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furyl; X⁻═ClO₄ ⁻) as a solid, m.p. 213°-214° C.

EXAMPLE 198 (a)

A reaction mixture containing 9-fluoro-benzo[b]quinolizinium perchlorate(0.69 g; 2 mmol) and 1,1-di[(1-p-methoxybenzyl)-pyrazol-3-yl]ethylene(0.8 g; 2 mmol) in 25 ml of aceto-nitrile was refluxed for 2 h undernitrogen. The reaction mixture was filtered, the filtrate wasconcentrated in vacuo, and the residue was triturated in methanol. Thesolid product was purified by silica gel column chromatography(methylene chloride/methanol, 9:1) to afford 0.92 g (32.5%) of6,11-ethano-12,12-di[(1-p-methoxy-benzyl)pyrazol-3-yl]-9-fluoro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR229## R⁷ ═9--F;X⁻ ═ClO₄ ⁻), as a solid.

(b)

A solution of 900 mg (1.3 mmol) of6,11-ethano-12,12-di[(1-p-methoxy-benzyl)-pyrazol-3-yl]-9-fluoro-6,11-dihydrobenzo[b]quinoliziniumperchlorate in 25 ml of trifluoroacetic acid was refluxed under nitrogenfor 24 h. The mixture was concentrated in vacuo and the residuedissolved in methanol/water. The aqueous layer was filtered, thefiltrate was concentrated in vacuo, and the product was converted to thecorresponding chloride by passing the salt through DOWEX® 1 ×2-200-Cl⁻(water/acetonitrile, 7/3). The salt was recrystallized from acetonitrileto afford 250 mg of6,11-ethano-12,12-di-(pyrazol-3-yl)]-9-fluoro-6,11-dihydrobenzo-[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═ ##STR230## R² ═9--F; X⁻═Cl⁻) as a solid, m.p. >300° C. (d).

EXAMPLE 199 (a) & (b)

A reaction mixture containing 10-hydroxy-benzo[b]quinoliziniumperchlorate (2.54 g; 8.6 mmol) and1-(3-furyl)-1-[1-(p-toluenesulfonyl)pyrazol-5-yl]ethylene (3 g; 9.5mmol) in 100 ml of nitromethane was refluxed for 3 h under nitrogen. Thereaction mixture was concentrated in vacuo, and the solid was purifiedby silica gel column chromatography (40% paw in ethyl acetate) andcrystallization of each isomer from isopropanol to afford:

Isomer 1:6,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfon-yl)-pyrazol-5-yl]-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.2 g; Example 199(a); Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═##STR231## R⁶ ═3-furyl; R⁷ ═10--OH; X⁻ ═ClO₄ ⁻), m.p.154°-158° C.

Isomer 2:6,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfon-yl)pyrazol-5-yl]-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (1.4 g; Example 199(b); Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵═3-furyl; R⁶ ═ ##STR232## R⁷ ═10--OH; X⁻ ═ClO₄ ⁻), m.p. 230°-262° C.

EXAMPLE 200

To a solution of 700 mg (1.1 mmol) of6,11-ethano-12-(3-furyl)-12-[1-(p-toluenesulfonyl)-pyrazol-5-yl]-10-hydroxy-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Example 199(a)) in 50 ml of methanol was added 1.5 ml (1.5mmol) of 1M t-BuOK in THF and the mixture was stirred for 3 hours. Themixture was filtered, the filtrate was concentrated in vacuo, and theresidue was converted to the corresponding chloride by passing the saltthrough DOWEX® 1×2-200-Cl⁻ (water/acetonitrile, 7/3). The salt wascrystallized from methanol to afford 390 mg of6,11-ethano-12-(3-furyl)-12-(pyrazol-5-yl)-10-hydroxy-6,11-dihydro-benzo[b]quinoliziniumchloride (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═5-pyrazolyl; R⁶ ═3-furyl; R⁷═10--OH; X⁻ ═Cl⁻) as a solid, m.p. 142°-148° C.

EXAMPLE 201 (a, b)

To a solution of 300 ml of nitric acid/sulfuric acid (1:1) cooled to-10° C. was added benzo[b]quinolizinium bromide (15 g; 57 mmol) over a10 minute period, and then the mixture was stirred for 25 minutes andpoured into ice. The mixture was filtered and the filtrate was treatedwith 200 ml of 35% sodium perchlorate solution. The product was filteredand dried to afford a mixture of 10-nitro-benzo[b]quinoliziniumperchlorate (Ex.201b) and 7-nitro-benzo[b]quinolizinium perchlorate (Ex201a)

(c, d)

A reaction mixture containing a mixture (1 g, 3.08 mmol) of10-nitrobenzo[b]quinolizinium perchlorate (Ex.201b) and7-nitrobenzo[b]quinolizinium perchlorate (Ex 201a) and1,1-di(3-furyl)ethylene (0.5 g, 3.09 mmol) in 20 ml of acetonitrile wasallowed to reflux under argon with stirring for 2 hours. The reactionmixture was concentrated in vacuo and the residue was triturated inether to yield 1.43 g of a solid mixture. The solid mixture waschromatographically separated using C-18 Waters Delta pack (55 ml/min;inj vol═0.5 ml, det; 270 nm, mobile phase=60% 0.01M sodium perchloratein water and 40% methanol) to afford:

Isomer A:6,11-ethano-12,12-di(3-furyl)-7-nitro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (53 mg; Example 201(c), Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶═3-furyl; R⁷ ═7--NO₂ ; X⁻ ═CIO₄ ⁻) as a solid, m.p. 260° C.

Isomer B:6,11-ethano-12,12-di(3-furyl)-10-nitro-6,11-dihydrobenzo[b]quinoliziniumperchlorate (116 mg; Example 201(d), Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵═R⁶ ═3-furyl; R⁷ ═10--NO₂ ; X⁻ ═ClO₄ ⁻) as a solid, m.p. 208° C.

EXAMPLE 202

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-1-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride of Example 168(c) with an excess of ClC(O)(CH₂)₇ CH═CH(CH₂)₇CH₃ in the presence of pyridine and 1,8-diazabicyclic [5.4.0] undec-7ene(DBU) will afford 6,11-ethano-12,12-di(3-furanyl)-1-[OC(O)(CH₂)₇CH═CH(CH₂)₇ CH₃ ]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I:R¹ ═1-[OC(O)(CH₂)₇ CH═CH(CH₂)₇ CH₃ ]; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-furanyl, X⁻ ═Cl⁻).

EXAMPLE 203

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-1-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride of Example 168(c) with an excess of ClC(O)CH═CHCO₂ CH₂ CH₃ inacetonitrite in the presence of cesium carbonate will afford6,11-ethano-12,12-di(3-furanyl)-1-[OC(O)CH═CHCO₂ CH₂ CH₃]-6,11-dihydrobenzo[b]quinolizinium chloride (Formula I: R¹═1-[OC(O)CH═CHCO₂ CH₂ CH₃ ]; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶ ═3-furanyl; X⁻═Cl⁻).

EXAMPLE 204

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-3-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride of Example 191(f) with an excess of octylbromide indimethylformamide in the presence of cesuim carbonate will afford6,11-ethano-12,12-di(3-furanyl)-3-n-octyloxy-6,11-dihydrobenzo[b]quinoliziniumchloride (Formula I: R¹ ═3--O(CH₂)₇ CH₃ ; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-furanyl; X⁻ ═Cl⁻).

EXAMPLE 205

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-3-hydroxy-6,11-dihydrobenzo[b]quinoliziniumchloride of Example 191(f) with an excess of ClC(O)C(CH₃)₂ CH₂C(O)O(CH₂)₇ CH₃ of example 194(c) in acetonitrile in the presence ofcesium carbonate will afford6,11-ethano-12,12-di(3-furanyl)-3-[OC(O)C(CH₃)₂ CH₂ C(O)O(CH₂)₇ CH₃]-6,11-dihydrobenzo]b]quinolizinium chloride (Formula I: R¹═3--[OC(O)C(CH₃)₂ CH₂ C(O)O(CH₂)₇ CH₃ ]; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-furanyl; X⁻ ═Cl⁻).

EXAMPLE 206 (a)

Following a procedure similar to that described in Example 164(b) butsubstituting 3-nitropyridine-2-carboxaldehyde for3-methoxypyridine-2-carboxyaldehyde it is contemplated that there can beprepared 2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-nitropyridine (FormulaX: R¹ ═3--NO₂ ; R² ═R⁷ ═H).

(b)

Following a procedure similar to that described in Example 164(c) butsubstituting 2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-nitropyridine for2-[1-hydroxy-(2'-hydroxymethyl)benzyl]-3-methoxypyridine it iscontemplated that there can be prepared 1-nitrobenzo[b]quinoliziniumperchlorate (Formula II: R¹ ═1--NO₂ ; R² ═R⁷ ═H; X⁻ ═ClO₄ ⁻).

(c)

Following a procedure similar to that described in Example 164(d) butsubstituting 1-nitrobenzo[b]quinolizinium perchlorate for1-methoxybenzo[b]quinolizinium perchlorate, it is contemplated thatthere can be prepared6,11-ethano-12,12-di(3-furanyl)-1-nitro-6,11-dihydrobenzo[b]quinoliziniumperchlorate.

(d)

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-1-nitro-6,11-dihydrobenzo[b]quinoliziniumperchlorate with stannous chloride and aqueous hydrochloric acid,followed by treatment of the 1-amino derivative thus formed withmethanesulfonyl chloride will afford6,11-ethano-12,12-di(3-furanyl)-1-methylsulfonylamino-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ 1--0 l-NHSO₂ CH₃ ; R² ═R³ ═R⁴ ═R⁷ ═H; R⁵ ═R⁶═3-furanyl; X⁻ ═ClO₄ ⁻).

EXAMPLE 207

It is contemplated that treatment of6,11-ethano-12,12-di(3-furanyl)-10-nitro-6,11-dihydrobenzo[b]quinoliziniumperchlorate with stannous chloride and aqueous hydrochloric acid,followed by treatment of the resulting 10-amino derivative withmethanesulfonyl chloride will afford6,11-ethano-12,12-di(3-furanyl)-10-methylsulfonylamino-6,11-dihydrobenzo[b]quinoliziniumperchlorate (Formula I: R¹ ═R² ═R³ ═R⁴ ═H; R⁵ ═R⁶ ═3-furanyl; R⁷═10--NHSO₂ CH₃ ; X⁻ ═ClO₄ ⁻).

Biological Test Results

Representative examples of the compounds of the invention have beenfound to possess valuable pharmacological properties. In particular,they have been found to bind to the PCP receptor and are thusnon-competitive blockers (antagonists) of the effects which excitatoryamino acids, such as glutamate, have upon the NMDA receptor. Thecompounds of the invention are thus useful in the treatment orprevention of neurodegenerative disorders such as Huntington's disease,Alzheimer's disease, amyotrophic lateral sclerosis, Down's Syndrome,senile dementia, glutaric acidaemia type I, multi-infarct dementia,Parkinson's disease, viral encephalopathies (which include, but are notlimited thereto, dementia associated with HIV infections) and neuronaldamage associated with uncontrolled seizures, as well as in thetreatment or prevention of neurotoxic injuries associated with ischemic,hypoxic or hypoglycemic conditions. Representative examples of suchischemic, hypoxic, or hypoglycemic conditions include strokes orcerebrovascular accidents, carbon monoxide poisoning, hyperinsulinemia,cardiac arrest, drownings, suffocation, spinal or head trauma, coronaryartery bypass graft, neonatal anoxic trauma, and perinatal asphyxia.

The compounds of the invention are particularly useful in the treatmentor prevention of neurotoxic injuries associated with ischemic, hypoxicor hypoglycemic conditions, and especially ischemic, hypoxic, orhypoglycemic conditions which are associated with stroke.

The pharmacological properties of representative examples of thecompounds of the invention was demonstrated by conventional in vitro andin vivo biological test procedures such as the following:

[³ H]TCP Radioreceptor Assay

[³ H]TCP binding to PCP recognition sites was performed as described byVignon et al. Brain Research 1983, 280, 194-197. Male Sprague-Dawleyrats were sacrificed by decapitation, and whole brains were homogenizedin 10 volumes (wt/vol) of cold Tris-HCl buffer (50 mM, pH 7.7) using aBrinkmann Polytron (setting 6, 30 sec). The homogenate was centrifugedat 40,000×g for 10 min at 4° C. The supernatant was decanted, and thehomogenization and centrifugation steps were repeated twice as describedabove. Following this, the pellet was resuspended in Tris-HCl (5 mM, pH7.7) at a tissue concentration of 0.5-0.75 g/mL, and one mL aliquotswere frozen at -70° C. until use. The binding characteristics for PCPrecognition sites were not altered by the freezing of membranesuspensions.

On the day of the assay, membrane aliquots were thawed, resuspended infresh 5 mM Tris-HCl buffer at a tissue concentration of 1 mg/mL, andstored on ice until use. Each assay tube contained 100 μl of [³ H]TCP ata final concentration of approximately 1 nM, 100 μL of variousconcentrations of the compounds of interest, 500 μL of the tissuesuspension and 300 μL of buffer to a final assay volume of 1 mL and afinal protein concentration of 0.5 mg/tube. Non-specific binding wasdefined by addition of a final concentration of 100 μM PCP to blanktubes. All tubes were incubated at room temperature for 25 min beforetermination of the reaction by rapid filtration over Whatman GF/B glassfiber filters that had been presoaked in a solution of 0.5%polyethylenimine for at least 1 hr prior to use. Filters were washedwith three 4 mL volumes of cold Tris buffer. Following addition ofscintillation cocktail, the amount of bound radioactivity was determinedby liquid scintillation spectrometry using a Beckman LS 5000TA liquidscintillation counter with an efficiency for tritium of approximately55%. Inhibition constants (K_(i) values) were calculated using theEBDA/LIGAND program (McPherson, J. Pharmacol. Meth. 1985, 14, 213-228),purchased from ElsevierBiosoft, Inc. Results are reported as the K_(i)values (in nM) which are expressed as the mean of at least two separatedeterminations; or as a percent (%) inhibition of binding at 10 μM.

Antagonism of NMDA-induced Neurotoxicity in Cultured Neurons

Preparation of Cultured Cortical Neurons

Pregnant, Swiss-Webster mice were obtained from Taconic Farms(Germantown, New York) and sacrificed 16 days post conception. Fetuseswere removed and placed in a sterile dish containing Hank's balancedsalt solution (HBSS), pH 7.4. Brain cortices were dissected, meningeswere removed, the tissue was minced and placed into a solution of HBSScontaining 0.25% (w/v) trypsin at 37° C. for 15 minutes. Tissue was thentriturated with a sterile pasteur pipet, diluted with minimal essentialmedia (Gibco 330-1430), pH 7.4, supplemented with 10% horse serum, 10%fetal calf serum, 2 mM 1-glutamine, 21 mM d-glucose, 2.2 g/L sodiumbicarbonate, 1000 U/mL penicillin, and 1,000 μg/mL streptomycin. Cellswere plated onto Falcon primaria 96 well plates at a final density of50,000 cells/well and incubated at 370C in the presence of 5% (v/v)carbon dioxide. After 5 days, plating media was replaced withmaintenance media containing minimal essential media (Gibco 330-1430),pH 7.4, supplemented with 10% horse serum, 10% 1-glutamine, 21 mMd-glucose, 2.2 g/L sodium bicarbonate, 1,000 U/mL penicillin, 1,000μg/mL streptomycin, and 10 μM cytosine arabinoside. On days 7 and 10,media was replaced with maintenance media as above lacking the cytosinearabinoside. Experiments were conducted on day 13.

Neuroprotection Assessment

Day 13 cultured cortical neurons were washed twice with minimalessential media, pH 7.4 and then exposed for 30 minutes to 500 μMN-methyl-D-aspartic acid (NMDA) with or without varying concentrationsof test agents. Dizocilpine (MK-801) at a final concentration of 10 μMMK-801 was routinely included as a positive control. MK-801 and testagents were prepared in minimal essential media supplemented with 21 mMd-glucose and 2.2 g/L sodium bicarbonate (MEM). After 30 minutes, mediawas replaced with MEM alone. Exposure of neurons to test agents waslimited to the NMDA treatment period. Twenty-four hours after removal ofNMDA, an aliquot of media from each well was removed for assessment ofcell injury by determining lactate dehydrogenase (LDH) activity by themethod of Wroblewski and LaDue Proc. Soc. Exp. Biol. Med. 1955, 90,210-213. The results are expressed as an IC₅₀ (in nM) value(concentration causing 50% inhibition) for the antagonism ofNMDA--induced neurotoxicity. Table 3 summarizes the results obtainedfrom the testing of representative compounds of the invention in the [³H]TCP radioreceptor assay as well as in the antagonism of NMDA-inducedneurotoxicity in cultured neurons.

                  TABLE 3                                                         ______________________________________                                                   [.sup.3 H]TCP Antagonism of                                                   K.sub.i (nM) or Percent                                                                     NMDA-induced                                         Example    inhibition    neurotoxicity                                        Number     @ 10 μm    (IC.sub.50 in nM)                                    ______________________________________                                        1F          7.58         --                                                   2(a)        123          --                                                   2(b)        262          --                                                   3(d)       14.1          --                                                   4(E)       5868          --                                                   5(c)       13.3          --                                                   5(d)        22           --                                                   6(c)        1.19         --                                                   6(d)        1.2           244                                                 7(b)        1.38          7.6                                                 7(c)        1.1          --                                                   8(c)        117          --                                                   9(b)        5.9          --                                                   10(c)      1100          --                                                   10(c-G)    4447          --                                                   10(c-k)     696          --                                                   11(d)       26           --                                                   11(F)       73           2550                                                 11(g)       18           2005                                                 12(b)       253          --                                                   13(a)       19           --                                                   13(b)       45           --                                                   14(c)       4.9          --                                                   15(c)       1.4          --                                                   17(b)       8.18          197                                                 18         19.5          --                                                   19(b)       6.8           102                                                 20(h)       7.15         --                                                   21         13.0          --                                                   22(b)       9.07         --                                                   23(c)      22%           --                                                   24(b)       8.39         --                                                   25(c)      39.3          --                                                   26         32.7          --                                                   27(E)      10.4          --                                                   28(c)      11.7          --                                                   29(c)      31%           --                                                   30(c)      22%           --                                                   31(c)      2207          --                                                   32(F)       468          --                                                   33(c)      1144          --                                                   34(b)      21.9          --                                                   35(c)      41.0          --                                                   36(c)       185          --                                                   37(E)      36.7          --                                                   38(c)      16.6          --                                                   39(c)       1.79         45.4                                                 40(b)       1.66          20                                                  42(E)      2267          --                                                   43(b)      45%           --                                                   44(b)      28122         --                                                   45(E)       491          --                                                   46(c)      31%           --                                                   47(d)       2.11          40                                                  48(b)       2.08          23                                                  49(E)      54%           --                                                   50(b)       1.24          22                                                  51(c)      22.3           83                                                  52(F)       1.82          39                                                  53(g)       93           --                                                   54(E)       52           --                                                   55(b)       104          --                                                   56          56           --                                                   57(d)       1.9           36                                                  58(c)      32%           >1,000                                               59(c)      3908          --                                                   60(e)       345          --                                                   61(c)       17           --                                                   62(c)       120          --                                                   63(c)      64%           --                                                   63(d)       10           1629                                                 64(f)       13            360                                                 65(c)       2.8          --                                                   66(g)        6           --                                                   67(e)       80           --                                                   67(g)      1481          --                                                   68(c)       1.5          --                                                   69(c)       0.9          --                                                   70(F)      3832          --                                                   71(F)       3.1          --                                                   111(a)      6.07         --                                                   111(b)     37.8          --                                                   158(f)      632          --                                                   159(h)     31%           --                                                   160(d)      453          --                                                   161(d)     3676          --                                                   162(d)      2.31         --                                                   163         7.54         --                                                   164(e)     18.9          --                                                   165        31.3          --                                                   166        61.1          --                                                   167(c)      7.68         --                                                   168(c)      306          --                                                   169         3.58         --                                                   170         232          --                                                   171(b)     10.2          26.5                                                 172        3377          --                                                   173(e)     1670          --                                                   174        23.7          --                                                   175(b)      119          --                                                   176(d)     39.4          --                                                   177        13.8          --                                                   178(d)     1430          --                                                   179(b)      259          --                                                   180(g)     19.9          --                                                   181(c)      6.36         11.4                                                 181(d)      6.15          55                                                  182(e)      159          --                                                   183(c)      2.72         --                                                   184(c)     12914         --                                                   184(d)     53%           --                                                   185(a)      4.55         32.6                                                 185(b)      6.29          53                                                  186(g)      122          --                                                   187(g)     63.7          --                                                   188(c)     23.6          --                                                   189(b)     22.5          --                                                   190(b)     10.7          --                                                   191(f)     1530          --                                                   192(g)      633          --                                                   193         2.13         11.8                                                 194(d)     71.3          --                                                   195(c)     12.6          30.8                                                 196(c)      4.11          80                                                  197(d)     13.8          --                                                   198(b)     11.7          --                                                   199(a)     27%           --                                                   200        11.5          --                                                   201(c)     3433          --                                                   201(d)     49.2          --                                                   ______________________________________                                    

Middle Cerebral Artery Occlusion (MCAo) Model with Reperfusion

A 3-vessel rat ischemia model similar to those that have beenextensively described in the literature (e.g. Stroke 17, 738-743 (1986),Stroke 20, 513-518 (1989)) was utilized. Under isoflurane anesthesia theright middle cerebral artery (via an approach through the temporalismuscle) and both common carotid arteries were reversibly occluded forvarying durations between 60 minutes and 120 minutes. Both male LongEvans hooded rats and male Sprague-Dawley rats weighing between 300 and420 grams were used. The animals' temperature was maintained throughoutthe study with heat lamps. A femoral vein and the ipsilateral femoralartery were cannulated for intravenous infusion and arterial bloodpressure measurements and blood samples. Infusions of the test compoundswere initiated 30 minutes prior to occlusion at a rate of 40 microlitersper minute. After reinitiation of blood flow the animals were allowed toregain consciousness. Six hours post-initiation of ischemia the animalswere sacrificed and the extent of neuronal damage was quantified withTTC staining. The results are expressed as a percent inhibition (±SEM)of infarct and penumbra region.

Table 4 summarizes the results obtained from the testing ofrepresentative compounds of the invention in the MCAO model.

                  TABLE 4                                                         ______________________________________                                                   Dose                                                               Example    (mg Test Compound/                                                                           % Inhibition                                        Number     kg/min)        (± SEM)                                          ______________________________________                                                   0.03           20 ± 7                                           39(c)      0.1            34 ± 6                                                      0.01            1 ± 31                                          40(b)      0.03           49 ± 25                                                     0.1            47 ± 18                                          68(c)      0.1            34 ± 14                                          ______________________________________                                    

The compounds of the invention can be prepared for pharmaceutical use byconventional pharmaceutical procedures that are well known in the art;that is, by formulating a pharmaceutical composition which comprisescompounds of the invention or their pharmaceutically acceptable saltstogether with one or more physiologically acceptable carriers,adjuvants, diluents or vehicles, for oral administration in solid orliquid form, parenteral administration, topical administration oraerosol inhalation administration, and the like.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, the activecompound is admixed with at least one inert diluent such as starch,calcium carbonate, sucrose or lactose. These compositions may alsocontain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water andliquid paraffin. Besides inert diluents such compositions may alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents.

Preparations according to the invention for topical administration oraerosol inhalation administration include dissolving or suspending acompound of the invention in a pharmaceutically acceptable vehicle suchas water, aqueous alcohol, glycol, oil solution or oil-water emulsion,and the like.

If desired, the compounds of the invention can further be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes, and microspheres.

The percentage of active component in such compositions may be varied sothat a suitable dosage is obtained. The dosage administered to aparticular patient is variable depending upon the clinician's judgmentusing as criteria: The route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus readily be determined bythe clinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

We claim:
 1. A compound of the formula: ##STR233## wherein: R¹ ishydrogen, or from one to four, the same or different, substituents inany of the 1⁻, 2⁻, 3⁻ or 4⁻ positions selected from the group consistingof lower-alkoxy, lower-alkyl, halogen, hydroxy, OC(O)alkyl-CH═CH-alkyl,OC(O) alkyl, OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy,OC(O)alkylC(O)Oalkyl, hydroxymethyl, nitro, amino andlower-alkylsulfonylamino or R¹ is a fused benzene ring;R² is hydrogen,lower-alkyl, cyano or lower-alkoxycarbonyl; R³ and R⁴ are independentlyhydrogen, or lower-alkyl; or R³ and R⁴ together form a cycloalkyl ring,or a lower alkylidene group; R⁵ and R⁶ are independently hydrogen,phenyl, furyl or benzofuryl; or R³ and R⁵, and/or R⁴ and R⁶ takentogether with the carbon atoms to which they are attached form abicyclic ring system of the formula A: ##STR234## wherein A is phenyl,or a 5-membered heterocyclic ring system and n is an integer from one tothree; R⁷ is hydrogen, or from one to four, the same or different,substituents in any of the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected fromthe group consisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro,hydroxy, lower-alkoxy, methylenedioxy, polyfluorolower-alkyl,OCO(CH₂)_(m) C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo,SO₃ ⁻, PO₃ H; PO₃ ⁻ cyano and polychlorolower-alkylOC(O)alkyl-CH═CH-alkyl, OC(O)-lower-alkenyl-C(O)alkyl, alkoxy,OC(O)alkylC(O))alkyl, halomethyl, hydroxymethyl, amino andlower-alkylsulfonylamino wherein m is an integer from one to four and/orR⁷ is a fused pyrazole ring; X⁻ is an anion; and, p is zero when R⁷ is anegatively charged radical and p is one when R⁷ is other than anegatively charged radical;or a pharmaceutically acceptableacid-addition salt of basic members thereof; or a solvate thereof; or astereoisomer thereof; with the following provisos a) at least one of R⁵and R⁶ when taken individually must be a phenyl, furyl or benzofurylgroup; b) when R³ and R⁵ or R⁴ and R⁶ together form a bicyclic ringsystem of formula A wherein A is phenyl and n is 1; R¹, R², R⁴, and R⁶or R¹, R², R³ and R⁵, respectively are hydrogen and X⁻ is BF₄ ⁻, R⁷ isother than hydrogen or 9-methyl; c) when R¹, R², R³, and R⁴ arehydrogen; R⁵ and. R⁶ are phenyl, and X⁻ is ClO₄ ⁻ or Br⁻ ; R⁷ is otherthan hydrogen.
 2. A compound according to claim 1 wherein:R¹ ishydrogen, or from one to four, the same or different, substituents inany of the 1⁻, 2⁻, 3⁻ or 4⁻ positions selected from the group consistingof lower-alkoxy, lower-alkyl and halogen; R² is hydrogen or lower-alkyl;R³ and R⁴ are independently hydrogen, or lower-alkyl; or R³ and R⁴together form a cycloalkyl ring, or a lower alkylidene group; R⁵ and R⁶are independently hydrogen, phenyl, furyl or benzofuryl; or R³ and R⁵,and/or R⁴ and R⁶ taken together with the carbon atoms to which they areattached form a bicyclic ring system of the formula A: ##STR235##wherein A is phenyl, or a 5-membered heterocyclic ring system and n isan integer from one to three; R⁷ is hydrogen, or from one to four, thesame or different, substituents in any of the 7⁻, 8⁻, 9⁻, or 10⁻positions selected from the group consisting of lower-alkyl,lower-alkanoyloxy, halogen, nitro, hydroxy, lower-alkoxy,methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m) C(O)Oalkyl,OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H; PO₃ ⁻ cyanoand polychlorolower-alkyl wherein m is an integer from one to; X⁻ is anunion; and p is zero when R⁷ is a negatively charged radical and p isone when R⁷ is other than a negatively charged radical;or apharmaceutically acceptable acid-addition salt of basic members thereof;or a solvate thereof; or a stereoisomer thereof; with the followingprovisos a) at least one of R⁵ and R⁶ when taken individually must be aphenyl, furyl or benzofuryl group; b) when R³ and R⁵ or R⁴ and R⁶together form a bicyclic ring system of formula A wherein A is phenyland n is 1; R¹, R², R⁴, and R⁶ or R¹, R², R³ and R⁵, respectively arehydrogen and X⁻ is BF₄ ⁻, R⁷ is other than hydrogen or 9-methyl; c) whenR¹, R², R³, and R⁴ are hydrogen; R⁵ and R⁶ are phenyl, and X⁻ is ClO₄ ⁻or Br⁻ ; R⁷ is other than hydrogen.
 3. A compound according to claim 2wherein: R⁵ and R⁶ are independently phenyl, furyl or benzofuryl; and R⁷is hydrogen, or from one to four, the same or different, substituents inany of the 7-, 8-, 9- or 10- positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedroxy, polyfluorolower-alkyl, SO₃ ⁻, andpolychlorolower-alkyl.
 4. A compound according to claim 3 wherein: R⁵and R⁶ are independently phenyl, furyl or benzofuryl; and wherein A isphenyl, or a 5-membered heterocyclic ring system and n is an integerfrom one to two.
 5. A compound according to claim 4 wherein R¹ ishydrogen, or one lower-alkyl substituent in any of the 1-, 2-, 3-,4-positions; and R⁷ is hydrogen, or from one to two, the same ordifferent substituents in any of the 7-, 8-, 9-, or 10-positionsselected from the group consisting of halogen, hydroxy, lower-alkoxy SO₃-- and polyfluorolower-alkyl.
 6. A compound according to claim 5wherein: R⁵ and R⁶ are independently phenyl, furyl or benzofuryl; andAis phenyl, or a 5- membered heterocyclic ring system.
 7. A compoundaccording to claim 6 wherein R¹ is hydrogen or 1-loweralkyl; and R⁷ ishydrogen or from one to two, the same or different, substituents in anyof the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected from the group consistingof bromine, fluorine, hydroxy, methoxy, isopropoxy, SO₃ ⁻ andtrifluoromethyl.
 8. A compound according to claim 7 wherein R¹ ishydrogen or 1-methyl; and R² is hydrogen, methyl or butyl; and R³ and R⁴are independently hydrogen, or methyl; or R³ and R⁴ together form acyclopropyl ring, or a methylidene group.
 9. A compound according toclaim 8 selected from the group consistingof:6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinolizinium X⁻ ; and6,11-ethano-6-methyl-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumX⁻.
 10. A compound according to claim 9 selected from the groupconsistingof:6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumchloride; and6,11-ethano-6-methyl-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumchloride.
 11. A compound according to claim 2 wherein R⁵ and R⁶ areindependently phenyl, furyl or benzofuryl; R¹ is hydrogen or onelower-alkoxy or halogen substituent in any of the 1-, 2-, 3- or 4-positions; and R⁷ is hydrogen, or from one to two, the same ordifferent, substituents in any of the 7-, 8-, 9, or 10- positionsselected from the group consisting of OC(O)alkyl, OCO(CH₂)_(m)C(O)Oalkyl, hydoxy, lower-alkoxy, methylenedioxy, halogen and nitro. 12.A compound according to claim 2 wherein R⁵ and R⁶ are independentlyphenyl, furyl or benzofuryl; R¹ is hydrogen, 1-halogen or1-lower-alkoxy; and R⁷ is hydrogen, or from one to two, the same ordifferent, substituents in any of the 7-, 8-, 9-, or 10- positionsselected from the group consisting of OC(O)(CH₂)₆ CH₃, OCO(CH₂) ₂C(O)OCH₂ CH₃, OC(O)CH₃, OC(O)t-Bu, hydroxy, methoxy, methylenedioxy,chloro, fluoro and nitro.
 13. A compound according to claim 11 whereinR¹ is hydrogen, 1-fluoro, or 1-methoxy; R² is hydrogen, or methyl; andR³ and R⁴ are independently hydrogen or methyl; or R³ and R⁴ togetherform a methylidene group.
 14. A compound according to claim 1 wherein R¹is from one to four, the same or different, substituents in any of the1-, 2-, 3- or 4- positions selected from the group consisting ofhydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,hydroxymethyl, nitro, amino and lower-alkylsulfonylamino; or R¹ is afused benzene ring.
 15. A compound according to claim 14 wherein:R¹ isone substituent in any of the 1-, 2-, 3- or 4- positions selected fromthe group consisting of hydroxy, and OC(O)alkyl; or R¹ is a fusedbenzene ring; and R², R³, R⁴ and R⁷ are hydrogen.
 16. A compoundaccording to claim 15 wherein R¹ is 1-hydroxy, 1-OC(O)CH₃ or a fusedbenzene ring.
 17. A compound according to claim 1 wherein R² is cyano orlower-alkoxycarbonyl.
 18. A compound according to claim 1 wherein R⁷ isfrom one to four, the same or different, substituents in any of the 7-,8-, 9- or 10- positions selected from the group consisting of OC(O)alkyl-CH═CH-alkyl, OC(O)-lower-alkenylC(O)Oalkyl, alkoxy,OC(O)alkylC(O)Oalkyl, halomethyl, hydroxymethyl, amino andlower-alkylsulfonylamino and/or R 7 is a fused pyrazole ring.
 19. Acompound according to claim 18 wherein R¹, R², R³, and R⁴ are hydrogen.20. A compound according to claim 19 wherein R⁷ is one substituentselected from the group consisting of OC(O)(CH₂)₇ HC═CH--(CH₂)₇ CH₃,OC(O)--CH═CH--C(O)OCH₂ CH₃, O(CH₂)₇ CH₃, O(CH₂)₇ CH₃, OC(O)C(CH₃)₂ CH₂C(O)OCH₂ CH₃, chloromethyl, hydroxymethyl, and OC(O)C(CH₃)₂ CH₂C(O)O(CH₂)₇ CH₃ ; and/or R⁷ is a fused pyrazole ring.
 21. Apharmaceutical composition which comprises a compound of the formula:##STR236## wherein: R¹ is hydrogen, or from one to four, the same ordifferent, substituents in any of the 1⁻, 2⁻, 3⁻ or 4⁻ positionsselected from the group consisting of lower-alkoxy, lower-alkyl,halogen, hydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,hydroxymethyl, nitro, amino and lower-alkylsulfonylamino or R¹ is afused benzene ring;R² is hydrogen, lower-alkyl cyano orlower-alkoxycarbonyl; R³ and R⁴ are independently hydrogen, orlower-alkyl; or R³ and R⁴ together form a cycloalkyl ring, or a loweralkylidene group; R⁵ and R⁶ are independently hydrogen, phenyl, furyl orbenzofuryl; or R³ and R⁵, and/or R⁴ and R⁶ taken together with thecarbon atoms to which they are attached form a bicyclic ring system ofthe formula A: ##STR237## wherein A is phenyl, or a 5-memberedheterocyclic ring system and n is an integer from one to three; R⁷ ishydrogen, or from one to four, the same or different, substituents inany of the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻ PO₃ H;PO₃ ⁻ cyano and polychlorolower-alkyl OC(O)alkyl-CH═CH-alkyl,OC(O)-lower-alkenyl-C(O)alkyl, alkoxy, OC(O)alkylC(O))alkyl, halomethyl,hydroxymethyl, amino and loweralkylsulfonylamino wherein m is an integerfrom one to four and/or R⁷ is a fused pyrazole ring; X⁻ is an anion; andp is zero when R⁷ is a negatively charged radical and p is one when R⁷is other than a negatively charged radical;or a pharmaceuticallyacceptable acid-addition salt of basic members thereof; or a solvatethereof; or a stereoisomer thereof; together with a pharmaceuticallyacceptable carder, adjuvant, diluent or vehicle, with the proviso thatat least one of R⁵ and R⁶ when taken individually must be a phenyl,furyl or benzofuryl group.
 22. A pharmaceutical composition according toclaim 21 wherein:R¹ is hydrogen, or from one to two, the same ordifferent, substituents in any of the 1⁻, 2⁻, 3⁻, 4⁻ positions selectedfrom the group consisting of lower-alkoxy, lower-alkyl, halogen; R² ishydrogen or lower-alkyl; R³ and R⁴ are independently hydrogen orlower-alkyl; or R³ and R⁴ together form a cycloalkyl ring, or alower-alkylidene group; R⁵ and R⁶ are independently hydrogen, phenyl,furyl or benzofuryl; or R³ and R⁵, and/or R⁴ and R⁶ taken together withthe carbon atoms to which they are attached form a bicyclic ring systemof the formula A: ##STR238## wherein A is phenyl, or a 5-memberedheterocyclic ring system and n is an integer from one to three; R⁷ ishydrogen, or from one to four, the same or different, substituents inany of the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H;PO₃ ⁻ cyano and polychlorolower-alkyl; wherein m is an integer from oneto four; X⁻ is an anion; and p is zero when R⁷ is a negatively chargedradical and p is one when R⁷ is other than a negatively chargedradical;or a pharmaceutically acceptable acid-addition salt of basicmembers thereof; or a solvate thereof; or a stereoisomer thereof;together with a pharmaceutically acceptable carrier, adjuvant, diluentor vehicle, with the proviso that at least one of R⁵ and R⁶ when takenindividually must be a phenyl, furyl or benzofuryl group.
 23. Apharmaceutical composition according to claim 22 wherein R⁵ and R⁶ areindependently phenyl, furyl or benzofuryl; and wherein A is phenyl, or a5- membered heterocyclic ring system and n is an integer from one totwo.
 24. A pharmaceutical composition according to claim 23 whereinR¹ ishydrogen, or one lower-alkyl substituents in any of the 1⁻, 2⁻, 3⁻ or 4⁻positions; R⁷ is hydrogen, or from one to two, the same or different,substituents in any of the 7-, 8-, 9-, or 10-positions selected from thegroup consisting of halogen, hydroxy, lower-alkoxy, SO₃ ⁻ andpolyfluorolower-alkyl; R⁵ and R⁶ are independently phenyl, furyl orbenzofuryl; and A is phenyl, or a 5- membered heterocyclic ring system.25. A pharmaceutical composition according to claim 23 wherein R¹ is1-lower-alkyl; R⁷ is hydrogen, or from one to two, the same ordifferent, substituents in any of the 7⁻, 8⁻, 9⁻, or 10⁻ positionsselected from the group consisting of bromine, fluorine, hydroxy,methoxy, isopropoxy, SO₃ ⁻, and trifluoromethyl; R⁵ and R⁶ areindependently phenyl furyl or benzofuryl; and A is phenyl, or a5-membered heterocyclic ring system.
 26. A pharmaceutical compositionaccording to claim 25 wherein R¹ is hydrogen or 1-methyl; R² ishydrogen, methyl, or butyl; and R³ and R⁴ are independently hydrogen, ormethyl; or R³ and R⁴ together form a cyclopropyl ring, or a methylidenegroup.
 27. A pharmaceutical composition according to claim 26 whereinthe compound is selected from the group consistingof:6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinolizinium X⁻ ; and6,11-ethano-6-methyl-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumX⁻.
 28. A pharmaceutical composition which comprises a compoundaccording to claim 10 together with a pharmaceutically acceptablecarrier, adjuvant, diluent or vehicle.
 29. A pharmaceutical compositionwhich comprises a compound according to claim 11 together with apharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
 30. Apharmaceutical composition which comprises a compound according to claim13 together with a pharmaceutically acceptable carrier, adjuvant,diluent or vehicle.
 31. A pharmaceutical composition which comprises acompound according to claim 14 together with a pharmaceuticallyacceptable carrier, adjuvant, diluent or vehicle.
 32. A pharmaceuticalcomposition which comprises a compound according to claim 16 togetherwith a pharmaceutically acceptable carrier, adjuvant, diluent orvehicle.
 33. A pharmaceutical composition which comprises a compoundaccording to claim 17 together with a pharmaceutically acceptablecarrier, adjuvant, diluent or vehicle.
 34. A pharmaceutical compositionwhich comprises a compound according to claim 18 together with apharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
 35. Apharmaceutical composition which comprises a compound according to claim20 together with a pharmaceutically acceptable carrier, adjuvant,diluent or vehicle.
 36. A method for the treatment of neurodegenerativedisorders or neurotoxic injuries which comprises administering to apatient in need of such treatment an effective amount of a compound ofthe formula: ##STR239## wherein: R¹ is hydrogen, or from one to four,the same or different, substituents in any of the 1⁻, 2⁻, 3⁻ or 4⁻positions selected from the group consisting of lower-alkoxy,lower-alkyl, halogen, hydroxy, OC(O)alkyl-CH═CH-alkyl, OC(O) alkyl,OC(O)-lower-alkenyl-C(O)Oalkyl, alkoxy, OC(O)alkylC(O)Oalkyl,hydroxymethyl, nitro, amino and lower-alkylsulfonylamino or R¹ is afused benzene ring;R² is hydrogen, lower-alkyl cyano orlower-alkoxycarbonyl; R³ and R⁴ are independently hydrogen, orlower-alkyl; or R³ and R⁴ together form a cycloalkyl ring, or a loweralkylidene group; R⁵ and R⁶ are independently hydrogen, phenyl, furyl orbenzofuryl; or R³ and R⁵, and/or R⁴ and R⁶ taken together with thecarbon atoms to which they are attached form a bicyclic ring system ofthe formula A: ##STR240## wherein A is phenyl, or a 5-memberedheterocyclic ring system and n is an integer from one to three; R⁷ ishydrogen, or from one to four, the same or different, substituents inany of the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H;PO₃ ⁻ cyano and polychlorolower-alkyl OC(O)alkyl-CH═CH-alkyl,OC(O)-lower-alkenyl-C(O)alkyl, alkoxy, OC(O)alkylC(O))alkyl, halomethyl,hydroxymethyl, amino and lower-alkylsulfonylamino wherein m is aninteger from one to four and/or R⁷ is a fused pyrazole ring; X⁻ is ananion; and p is zero when R⁷ is a negatively charged radical and p isone when R⁷ is other than a negatively charged radical;or apharmaceutically acceptable acid-addition salt of basic members thereof;or a solvate thereof; or a stereoisomer thereof; with the followingproviso that at least one of R⁵ and R⁶ when taken individually must be aphenyl, furyl or benzofuryl group.
 37. A method according to claim 36wherein:R¹ is hydrogen, or from one to four, the same or different,substituents in any of the 1⁻, 2⁻, 3⁻ or 4⁻ positions selected from thegroup consisting of lower-alkoxy, lower-alkyl, and halogen; R² ishydrogen, or lower-alkyl; R³ and R⁴ are independently hydrogen, orlower-alkyl; or R³ and R⁴ together form a cycloalkyl ring, or alower-alkylidene group; R⁵ and R⁶ are independently hydrogen, phenyl,furyl or benzofuryl; or R³ and R⁵, and/or R⁴ and R⁶ taken together withthe carbon atoms to which they are attached form a bicyclic ring systemof the formula A: ##STR241## wherein A is phenyl, or a 5-memberedheterocyclic ring system and n is an integer from one to three; R⁷ ishydrogen, or from one to four, the same or different, substituents inany of the 7⁻, 8⁻, 9⁻, or 10⁻ positions selected from the groupconsisting of lower-alkyl, lower-alkanoyloxy, halogen, nitro, hydroxy,lower-alkoxy, methylenedioxy, polyfluorolower-alkyl, OCO(CH₂)_(m)C(O)Oalkyl, OC(O)alkyl, C(O)Oalkyl, CO₂ ⁻, carboxy, sulfo, SO₃ ⁻, PO₃ H,PO₃ ⁻, cyano, and polychlorolower-alkyl wherein m is an integer from oneto four; X⁻ is an anion; and p is zero when R⁷ is a negatively chargedradical and p is one when R⁷ is other than a negatively chargedradical;or a pharmaceutically acceptable acid-addition salt of basicmembers thereof; or a solvate thereof; or a stereoisomer thereof; withthe proviso that at least one of R⁵ and R⁶ when taken individually mustbe a phenyl, furyl or benzofuryl group.
 38. A method according to claim37 wherein R⁵ and R⁶ are independently phenyl, furyl or benzofuryl; andwherein A is phenyl, or a 5-membered heterocyclic ring system and n isan integer from one to two.
 39. A method according to claim 38 whereinR¹is hydrogen, or one lower-alkyl substituents in any of the 1⁻, 2⁻, 3⁻ or4⁻ positions; R⁷ is hydrogen, or from one to two, the same or different,substituents in any of the 7-, 8-, 9-, or 10-positions selected from thegroup consisting of halogen, hydroxy, lower-alkoxy, SO₃ ⁻ andpolyfluorolower-alkyl; R⁵ and R⁶ are independently phenyl, furyl orbenzofuryl; and A is phenyl, or a 5- membered heterocyclic ring system.40. A method according to claim 39 wherein R¹ is hydrogen, or1-lower-alkyl; R⁷ is hydrogen, or from one to two, the same ordifferent, substituents in any of the 7-, 8-, 9-, or 10- positionsselected from the group consisting of bromine, fluorine, hydroxy,methoxy, isopropoxy, SO₃ ⁻, and trifluoromethyl; R⁵ and R⁶ areindependently phenyl, furyl or benzofuryl; and A is phenyl, or a5-membered heterocyclic ring system.
 41. A method according to claim 40wherein: R¹ is hydrogen or 1-methyl; R² is hydrogen, methyl, or butyl;and R³ and R⁴ are independently hydrogen, or methyl; or R³ and R⁴together form a cyclopropyl ring, or a methylidene group.
 42. A methodaccording to claim 37 wherein the compound is selected from the groupconsistingof:6,11-ethano-12,12-diphenyl-6,11-dihydrobenzo[b]quinolizinium X⁻ ; and6,11-ethano-6-methyl-12,12-diphenyl-6,11-dihydrobenzo[b]quinoliziniumX⁻.
 43. A method according to claim 36 for the treatment ofneurodegenerative disorders.
 44. A method according to claim 36 for thetreatment of neurotoxic injuries.
 45. A method according to claim 44wherein said neurotoxic injuries are associated with ischemic, hypoxic,or hypoglycemic conditions.
 46. A method according to claim 45 whereinsaid ischemic, hypoxic, or hypoglycemic conditions are associated withstroke.
 47. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim11.
 48. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim14.
 49. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim14.
 50. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim16.
 51. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim17.
 52. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim18.
 53. A method for the treatment of neurodegenerative disorders orneurotoxic injuries which comprises administering to a patient in needof such treatment an effective amount of a compound according to claim18.